AUTHORS:
Hema Dave, MD, MPH, Attending Physician, Division of Blood and Marrow Transplantation, Children’s National Health System, Washington, DC
Lydia Pecker, MD, Clinical Fellow, Pediatric Hematology and Oncology, Division of Cancer and Blood Disorders, Children’s National Health System, Washington, DC
PHYSICIAN EDITOR:
Ann Dietrich, MD, FAAP, FACEP, Professor of Pediatrics, Ohio State University; Attending Physician, Nationwide Children's Hospital; Associate Pediatric Medical Director, MedFlight
PEER REVIEWER:
Taryn R. Taylor, MD, FAAP, FACEP, Assistant Professor of Pediatrics and Emergency Medicine, Emory University School of Medicine, Atlanta, GA
Executive Summary
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Risk factors for developing acute chest syndrome include respiratory infections, treatment with opiates, and splinting due to chest or abdominal pain.
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Thrombocytopenia is uncommon and should alert the physician to the possibility of hepatic or splenic sequestration
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Hydroxyurea is expected to modify hematologic parameters: Hemoglobin may be higher than expected (9-10 g/dL in patients with HbSS) and reticulocyte count low. Macrocytosis is expected. Thrombocytopenia and neutropenia are common side effects and may indicate a supratherapeutic dose.
Sickle cell disease is a very common inherited genetic disorder in the United States, and patients with this disorder frequently present to acute care centers for evaluation and treatment. These patients require expert care to prevent and avert the life-threatening consequences of their disease. Many advances have been made that have improved the life expectancy for patients with this disease and emergency medicine physicians must be aware of these new modalities for diagnosis and treatment to optimize care. This article comprehensively reviews the current standard of care for children with sickle cell disease.
— Ann M. Dietrich, MD, FAAP, FACEP, Editor
Sickle cell disease (SCD) is the most common inherited genetic disorder in the United States, and the population frequency of the HbS allele is increasing.1 SCD was first described in Chicago in 1910 in a West Indian dental student named Walter Clement Noel. Since then, progress in SCD diagnosis and treatment has improved care for children with SCD. Notable advances include a national newborn screening program, infection prevention with penicillin prophylaxis and vaccines against encapsulated organisms, hydroxyurea to decrease painful crises and possibly ameliorate end-organ injury associated with SCD,2 chronic red blood cell transfusions to reduce stroke risk, and cure with hematopoietic stem cell transplant (HSCT).1,3-8 Despite these advances, life expectancy remains in the fifth to sixth decade for those with hemoglobin SS disease.9-12
SCD patients depend on urgent and emergent hospital-based care for treatment of the life-threatening consequences of their disease.13-18 Physicians’ attitudes toward these patients leads to differences in pain management and outcomes.19,20 Recent publications about the care of patients with SCD include the National Institute of Health’s updated SCD evidence-based practice guidelines and reviews of emergency care for adult sickle cell patients and atypical presentations in children with SCD.13,21,22 23 This article will review common emergencies in pediatric SCD.
Classification
Multiple genotypes cause SCD with variable phenotypic expression. Sickle cell anemia refers to the homozygous inheritance of the abnormal hemoglobin sickle (HbS) gene. Table 1 shows ß-globin mutations causing the different clinical phenotypes of SCD.
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Table 1. Classification of Sickle Cell Disease |
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Genotype |
Hemoglobin Quantification in % |
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HbAS (trait) |
50 |
45 |
2 |
- |
2 |
Normal |
|
HbSS |
- |
96 |
2 |
- |
2 |
Severe, Hb 6-9 g/dL |
|
HbSC |
- |
48 |
3 |
47 |
2 |
Moderate severe; stroke much less common. |
|
HbSß+ |
6 |
85 |
5 |
- |
4 |
Moderate severe, Hb 10-13 g/dL |
|
HbSß0 |
- |
93 |
2 |
- |
5 |
Severe, Hb 6-9 g/dL |
|
|
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HbA |
HbS |
HbF |
HbC |
HbA2 |
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HbAA (normal) |
96 |
- |
2 |
- |
2 |
Normal |
Pathophysiology
Normal adult hemoglobin (HbA) is a tetramer of four proteins, two α- and two ß-globin chains. In SCD, abnormal ß-globin chains called hemoglobin sickle are produced as a result of the substitution of valine for glutamic acid on position 6 of the beta globin gene on chromosome 11. The interactions between mutated ß-chains leads to abnormal protein folding and polymerization, causing red blood cell (RBC) sickling. The severity of sickling depends on the inheritance pattern of the HbS gene (see Figure 1). HbS polymerization is exacerbated by changes to temperature, pH, and hydration. Interactions between rigid erythrocyte polymers and the vascular endothelium drives platelet activation and inflammation, causing vascular dysfunction.24
Two major pathophysiological processes cause the clinical manifestations of SCD: hemolytic anemia and vaso-occlusion with ischemia-reperfusion (I/R) injury.25 The serologic consequences of hemolysis are anemia, hyperbilirubinemia, and reticulocytosis. Hemolysis also contributes to vasculopathy that is associated with pulmonary hypertension, renal hyper filtration, chronic leg ulcers, and priapism in SCD. Free plasma Hb causes endothelial damage and depletes nitric oxide, further aggravating vasculopathy.1 I/R injury causes inflammation and worsens endothelial dysfunction, contributing to vaso-occlusive pain crises. (See Figure 2.)
Laboratory Findings
Common laboratory evaluations useful in patients with SCD are described in Table 2. Rapid interpretation of the complete blood count (CBC) and reticulocyte count in patients with SCD helps identify when immediate intervention is required. For each parameter, comparison with patients’ baseline guides interpretation.
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Table 2. Common Studies in Patients with Sickle Cell Disease |
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Reticuloctye Count |
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Liver Function Tests |
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Hemoglobin Quantitation |
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Blood culture |
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Chest XR |
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Head CT |
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Diffusion Weighted MRI |
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CBC |
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Hemoglobin: SCD patients have baseline hemoglobin that varies based on genotype. Knowing the patient’s genotype and baseline hemoglobin is essential for interpreting the CBC. Many parents know their child’s usual “normal” hemoglobin. For children with HbSS, this is usually 7-9 g/dL. A robust reticulocyte count is essential for children with SCD, as sickled RBC’s life span is only 7-10 days compared to the 120 days of a typical RBC. Therefore, any child with SCD and a low (uncompensated) reticulocyte count with anemia may develop life-threatening anemia, called an aplastic crisis.
Platelets: Thrombocytosis is common in patients with SCD because of underlying inflammation. Thrombocytopenia is uncommon and should alert the physician to the possibility of hepatic or splenic sequestration.
Leukocytes: Many patients with SCD have a modest leukocytosis at baseline due to chronic inflammation. Marked leukocytosis should always be concerning for infection in patients with SCD.
Hemolysis markers: Lactate dehydrogenase, aspartate aminotransferase, unconjugated bilirubin, and reticulocyte count are serological markers of hemolysis and may be elevated at baseline in patients with SCD.
Interpreting the CBC of children treated with hydroxyurea (HU) is increasingly important. HU is expected to modify hematologic parameters: Hemoglobin may be higher than expected (9-10 g/dL in patients with HbSS) and reticulocyte count low. Macrocytosis is expected. Thrombocytopenia and neutropenia are common side effects of HU and may indicate a supratherapeutic dose.26 At least one case of significant accidental HU ingestion is reported without injury to the child.27
Clinical Manifestations of Sickle Cell Emergencies by System: Pulmonary
Acute Chest Syndrome. Acute chest syndrome (ACS) is a clinical diagnosis defined as a new infiltrate on chest X-ray in the presence of fever, cough, tachypnea, or chest pain. Underlying infection and bone infarct with fat emboli likely contribute to the evolution of this life-threatening complication of SCD. ACS may progress rapidly to multi-organ failure and is a leading cause of death in children and adults with SCD. Because of the risks associated with ACS and its unpredictable course, conservative management with admission for intervention or observation irrespective of disease severity is normative.28,29 Risk factors for developing ACS include respiratory infections, treatment with opiates, and splinting due to chest or abdominal pain.30
Treatment of ACS includes empiric antimicrobial coverage with a third-generation cephalosporin and a macrolide to cover community-acquired and atypical pneumonia as well as encapsulated organisms. In treating pain and dehydration, the clinician balances the benefit of aggressive pain treatment and fluid resuscitation against the risks of respiratory depression with opiate administration and fluid overload. Hydration with fluids at a rate between two-thirds and maintenance is sufficient. In the absence of an additional indication for transfusion, such as severe anemia or worsening clinical status, transfusions are not emergently indicated.31 A recent Cochrane Review concluded that insufficient evidence supports the empiric use of short-acting bronchodilators for SCD patients; however, given the incidence of comorbid asthma in children with SCD, a trial of therapy may be warranted.32-34 Historically, corticosteroids were used to treat ACS, but this practice is discouraged because corticosteroids are associated with severe rebound vaso-occlusive crises, stroke, and death. If they must be used due to severity of respiratory distress, conservative tapering is indicated.35
Asthma. The prevalence of asthma in children with SCD is similar to the prevalence in children of African descent in the United States.36 Children with SCD and asthma have higher SCD morbidity and increased rates of ACS, vaso-occlusive pain crisis (VOC), and premature mortality compared to those without asthma.37 Wheezing is common in children with SCD and may portend intrinsic SCD-related pulmonary disease rather than reactive airway disease. Acute episodes of wheezing in the setting of ACS should be managed with inhaled beta-2 agonists and, if necessary, corticosteroids with careful tapering.38 See Table 3 for specific management.
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Table 3. Management of Wheezing in Children with SCD |
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b. ACS with no prior h/o asthma |
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Bronchodilator and short course steroids; start controller medications for those with persistent asthma |
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* Systemic steroids longer than 1-2 days are associated with rebound pain, fat necrosis, and intracranial hemorrhage. Adapted from Glassberg et al. Wheezing in children with sickle cell disease. Curr Opin Pediatr 2014;26:9-18. |
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Bronchodilator and short course steroids |
Musculoskeletal
Vaso-occlusive pain crisis. Acute VOC pain crisis is the hallmark of SCD. Patients present with severe pain as early as 6 months of age. Of note, most sickle cell-related pain in children is managed at home with supportive care and oral pain medications. Hydroxyurea is the only medicine that decreases the pain crisis frequency.6,26,39,40 In older children and adolescents, VOC pain is often symmetric and regional, usually in the back or extremities, although it can affect any part of the body. Parents are often familiar with their child’s pattern of pain. Verbal children may be able to describe the pain as typical or atypical for their painful crisis. Identification of children experiencing painful crises facilitates early triage, prompt pain medication administration, and evaluation for potential alternate etiologies of pain such as ACS, cholecystitis, osteomyelitis, constipation, and osteonecrosis.
Dactylitis, or hand-foot syndrome, is a painful complication of SCD affecting young children, typically 6 months to 2 years of age and rarely after 5 years of age. Ischemia and infarction of the metacarpals and phalanges cause painful and often symmetric swelling of hands and/or feet and sometimes fever. This may occur in isolation or during a VOC event, and, although dactylitis may cause fever, blood culture and parenteral antibiotics are indicated (see: Fever).
Evaluation
On physical exam, VOC pain is not usually accompanied by edema or erythema, although patients may be tender at the site of pain. Evaluating and treating sickle cell VOC is vexing to clinicians because of the dependence on subject pain reports. Pain scales may not accurately reflect patient pain, and over reliance on such scales may lead to under treatment of pain and seriously compromise patient care.3 Vital signs and general appearance may be discordant with the patient’s report of pain. In these instances, communication between parents, patients, and, whenever possible, the primary hematology team help optimize the pain management plan.
Management
Rapid triage, evaluation by a clinician, and early administration of opioid analgesia are the mainstay of treatment for an acute pain crisis.21 Isotonic fluids should be administered only if patients appear dehydrated as they may exacerbate hemolysis; otherwise, half normal saline at maintenance rate is the mainstay. Clinical care pathways for VOC expedite management, decrease time to first analgesia, and improve patient satisfaction.41 Laboratory evaluation should include CBC, reticulocyte count, liver function tests, and bilirubin levels. No laboratory values can confirm a painful crisis. CRP and LDH are often elevated, signifying the non-specific presence of inflammation and hemolysis, respectively. Trials are underway to identify genes that are upregulated in acute painful crisis.
When possible, ED staff should have access to pain plans developed by the patient in consultation with his/her primary hematologist or primary provider. Individualized pain plans decrease hospitalization and readmission rates.8 Mild pain can be managed with NSAIDs and hydration, but severe pain requires opiates. Morphine and hydromorphone are the drugs most widely used, and when renal function is adequate, ketorolac may be used as adjunct therapy.21 If available and developmentally appropriate, a patient-controlled analgesia pump should be initiated promptly. Non-pharmacological measures, such as distraction, acupressure, relaxation, and music, can be helpful in early or mild pain but no randomized clinical trials compare their efficacy to medication.9 Other agents under investigation for treatment of VOC in children include low-dose subcutaneous ketamine,42,43 nitric oxide,44 and magnesium.1,5,45
Avascular necrosis (AVN). AVN is a debilitating condition caused by osteonecrosis from compromised osseous circulation. Blood hyperviscosity46 and RBC deformability47 play an important roles in its pathogenesis. The femoral head is the most commonly affected site, causing severe and chronic hip pain. However, AVN may also occur in other joints such as the spine and shoulders. AVN is more commonly seen in HbSS in children < 15 years of age and those with a high hematocrit.48 Treatment is usually conservative until surgical replacement is required.4,6-8,21
Infection
Fever and sepsis. Children with SCD are functionally asplenic and at increased risk of serious bacterial infections.10-12,49 They are at particular risk for infection with encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenza, and Neisseria meningitidis) and enteric Gram-negative organisms such as Salmonella. Penicillin prophylaxis and 23-valent pneumococcal vaccination have decreased the rate of bacteremia among children with SCD.13-18,50 Nevertheless, any child with SCD and fever should be screened for bacterial infection with at least an aerobic blood culture. A complete history of a febrile child with SCD includes penicillin adherence for children younger than 5 years old, and attention to pneumococcus, H. influenza, and meningococcal vaccination status. Even in an optimally prophylaxed and vaccinated child, penicillin-resistant organisms or non-vaccine pneumococcal serotypes may cause infection.51
The 2014 National Heart, Lung, and Blood Institute (NHLBI) guidelines define fever as a temperature > 38.5° C or 101.3° F. According to the new national standards, any child meeting this condition at home or in a health care setting needs: 1) immediate evaluation with a complete medical history and physical, CBC with reticulocyte count, blood culture and to consider a urine culture; and 2) prompt administration of a parenteral antibiotic that covers S. pneumoniae and Gram-negative organisms such as a third-generation cephalosporin. The NHLBI recommends admission of any ill-appearing children and those with risk factors for bacteremia, including infants younger than 6 months of age, CBC different from baseline, missed penicillin doses, pulmonary disease, or concern for ability to return for a second dose of antibiotics. Well-appearing children may be managed as outpatient if adequate resources for follow-up exist.
Given the increasingly diverse population of children with SCD in the United States, infections such as Ebola, malaria, or dengue must be considered if a child’s travel history is consistent with potential exposure. Salmonella and Staphylococcus aureus cause osteomyelitis and should be considered in patients with fever and focal bony tenderness.19-21
Spleen
Splenic Sequestration. Splenic sequestration is an acute enlargement of the spleen with a fall in hemoglobin at least 20% from baseline. Reticulocyte count may be normal or increased,53 and thrombocytopenia is common, as platelets are also sequestered in the spleen. Diagnosis of splenic sequestration is clinical. Imaging is not required. The median age in HbSS and HbSß? is 1-4 years, with episodes seen as early as 5 weeks.21,54 In patients with HbSC and HbSß+, splenic involution is delayed and sequestration may present at an older age.25,54 Parents are taught spleen palpation maneuvers because early identification and prompt treatment helps prevent severe presentations and death.28,29,55
Sickled red blood cells trapped in the splenic sinusoids cause mechanical obstruction leading to the clinical signs of sequestration: abdominal distension, pallor and hemodynamic instability with tachycardia, and hypotension. Alternative diagnoses in children with anemia and thrombocytopenia include transient aplastic crisis and chronic hypersplenism. Immediate resuscitation with intravenous fluids and emergent blood transfusion can be lifesaving. Transfusions should be administered in small aliquots. This is because the spleen releases RBCs and patients “auto-transfuse,” releasing RBCs into the peripheral circulation and placing transfused patients at risk for hyperviscosity and stroke. Recurrence of splenic sequestration is common, recurring in 50-75% of cases. In some instances, splenectomy is indicated.54,56
Transient aplastic crisis. Human parvovirus B19 is now known to be the cause of transient aplastic crises in patients with SCD. Because SCD patients depend on their reticulocytes to maintain their hemoglobin, the reticulocyte suppression associated with parvovirus B19 can cause life-threatening anemia. Patients present with sudden onset of pallor, fatigue, and weakness and may have signs of high-output heart failure. Reticulocytopenia with anemia supports this diagnosis. Treatment is supportive, and RBC transfusion may be required. In severely anemic patients, RBC transfusion should be administered slowly, in small aliquots, as patients may have compensated for their severe anemia. Rapid transfusion may trigger high-output heart failure.57 During the recovery phase, the CBC shows reticulocytosis with severe anemia, making splenic sequestration another possible differential concern.
If parvovirus infection is suspected in a patient in the ED, the patient should be isolated from common areas and strict droplet precautions applied. Pregnant or potentially pregnant staff should be assigned to other patients, as parvovirus may cause severe fetal complications.58
Gastrointestinal and Hepatobiliary
Gastrointestinal complications of SCD include cholelithiasis, abdominal VOC, and constipation. In young children especially, physical exam may be insufficient to distinguish these etiologies from causes of acute abdomen common in all children vs those particular to children with SCD. Here we discuss gastrointestinal complications of SCD, with the caution that these children may, like children without SCD, have acute abdominal pathology unrelated to SCD.52
Cholelithiasis/cholecystitis. Cholelithiasis occurs in 26-58% of patients with HbSS disease and is associated with higher baseline hyperbilirubinemia. Patients with cholelithiasis present with colicky abdominal pain that localizes to the upper right quadrant. The best first test for evaluation is ultrasound; however, the test is not sensitive for gallstones. Emergency management for pain associated with cholelithiasis is supportive with hydration and opiates. Because of chronic cholelithiasis, patients are at risk for cholecystitis. Primary management of this infectious complication of cholelithiasis includes parenteral antibiotics to cover anaerobic and gram-negative abdominal organisms; piperacillin-tazobactam is commonly used. For symptomatic cholelithiasis, cholecystectomy is often delayed until the patient is stable and asymptomatic, although this practice is debated.52
Neurologic
Stroke. Children with SCD are 333 times more likely to suffer a stroke than children in the general population.59 Approximately 11% of children with SCD develop overt stroke before the age of 20 years. Children are at greatest risk from 2-5 years of age. Stroke is most common in HbSS and less in HbS-ß-thalassemia or HbSC disease.59 Ischemic strokes constitute 54% of cerebrovascular accidents (CVA) in SCD patients and are more common in the very young and old. Hemorrhagic strokes are more common among patients with SCD in their 20s.60 About 10-30% of children develop silent cerebral infarcts with T2 signal abnormalities in the white matter in the absence of overt neurological deficits.61 Routine screening with transcranial Doppler allows early identification of children at risk for stroke and permits intervention with chronic RBC transfusion.62 Children with a history of stroke may receive chronic blood transfusion to maintain HbS at less than 30%. This treatment reduces the risk of recurrent stroke from 70-90% to less than 20-30%.63 Hydroxyurea and stem cell transplant are treatment options beyond the scope of this review.
Pathophysiology
Ischemic strokes initially were thought to result from hyperviscosity of sickled red cells with subsequent vasculopathy and stenosis of the large cerebral vessels branching off of the Circle of Willis.60 It is now known that the mechanism is not that simple. It's an interplay of adhesion of sickled cells to the vascular endothelium and resultant ischemia-reperfusion injury that triggers release of prothrombotic factors resulting in microvascular occlusion and thrombosis.24,60,64-66 Hemorrhagic stroke may result from rupture of the prevalent multiple small aneurysms, especially in the posterior circulation. Risk factors for CVA are described in Table 4.
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Table 4. Risk Factors for Stroke in SCD |
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Ischemic Stroke |
Hemorrhagic Stroke |
SCI |
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Adapted from: Verduzco LA, Nathan DG. Sickle cell disease and stroke. Blood 2009;114:5117-5125. |
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Prior ischemic stroke h/o TIA h/o SCI Nocturnal hypoxemia Recent ACS, fever or exchange transfusion within 2 weeks of stroke
TCD velocity ≥ 200cm/sec |
Hypertension Older age Low Hb |
Baseline leukocytosis Baseline low Hb h/o seizures |
Clinical Presentation
Children having a CVA may present with seizures and motor deficits, and posterior circulation lesions may present with ataxia. In some children, headache may be the only symptom. Hemorrhagic strokes present with severe headaches caused by meningeal irritation and increased intracranial pressure. In high-risk SCD patients, such as those with HbSS, a low threshold for brain imaging is warranted.30,67
Management
Stroke is a medical emergency and must be managed with an interdisciplinary team including the ED physician, radiologist, neurologist, and hematologist. The specialists responsible for exchange transfusion vary by center and may be transfusion medicine specialists or pathologists. These specialists should also be notified of any child with a likely stroke.
Initial assessment should focus on stabilization of the patient and monitoring vital signs. Where available, a stroke algorithm should be used. Initial management includes a detailed history and physical examination, CBC, reticulocyte count, type and screen, basic metabolic panel, and coagulation profile. A non-contrast CT scan determines hemorrhagic stroke and is often the first test available. MRI and MRA with diffusion-weighted images are the gold standard for identifying the timing and location of ischemic stroke and should be performed for all children with SCD in whom stroke is a differential concern.63 Overnight MRI may be delayed due to availability of technicians or need for patient anesthesia. This need not delay manual or automated exchange transfusion. If technical or logistical challenges also obstruct exchange transfusion, simple transfusion may be used, but should not raise the hemoglobin to more than 10 g/dL due to the risk that hyperviscosity that may cause secondary stroke.31,63 There is no role for antifibrinolytics or anticoagulation.
Genitourinary
Priapism. Priapism (prolonged erection unrelated to sexual stimulus) is common in boys and men with SCD and is responsible for 65% of all cases of major priapism (lasting > 4 hours).32-34,68 At least 35% of men with SCD experience priapism.21,35 The mean age at first attack is 15 years, and 75% will have their first attack before 20 years of age.36,69
Priapism is a urologic emergency. Recurrent, untreated episodes cause long-term damage to penile structure and function.37,70 Prolonged intervals of priapism (> 48 hours) are associated with increased risk of erectile dysfunction, regardless of intervention. Priapism is incompletely understood but likely attributable to penile venous stasis, hypoxia, and ischemia.38,71
It is important to ascertain the duration of symptoms, degree of pain, history of priapism, drug use (recreational or medicinal), and self-treatment attempts. Combined with careful physical exam, this may exclude alternate etiologies for priapism, even in patients with SCD.37,70 Initial laboratory testing includes CBC, hemolysis markers, and type and screen.
No large randomized trials guide emergency management of sickle cell-related priapism. The emergent goal of treatment is detumescence. Initial management is conservative with hydration, oxygen, and pain control with opiates. Oral alpha-adrenergic agents such as pseudoephedrine (0.5 mg/kg to a maximum dose of 30 mg) may be used, although no trial definitively demonstrates efficacy.21 For major priapism (> 4 hours) or priapism unresponsive to conservative intervention, urology consultation should be obtained for potential corporeal aspiration and/or alpha-adrenergic intracorporeal injection.41,68 Blood transfusions are associated with adverse neurologic events in the setting of priapism and should be avoided if possible.21,70 The need for anesthesia to emergently treat priapism may require a blood transfusion and should prompt hematology consultation.
Surgery
Whenever possible, children with SCD requiring emergent surgery should be transfused in consultation with a hematologist prior to receiving anesthesia. In a trauma setting this may not be possible. The goal of transfusion is to reduce the fraction of sickle cells in circulation. Transfusion prior to low-risk surgery reduces the risk of postoperative complications, particularly for patients with HbSS.72 As a rule of thumb, 5 mL/kg of packed RBCs raises the hemoglobin 1 g/dL. In patients with a hemoglobin level close to 10 g/dL, simple transfusion may not be possible due to the risk of hyperviscosity.
Conclusion
Clinicians in the ED play a critical role in identifying and treating the many complications of SCD. A careful patient history, physical exam, and review of laboratory testing should guide the ED clinician’s evaluation and treatment of SCD patients. Children with SCD benefit from treatment algorithms for many common complications of their disease. Whenever possible, access to records and communication with treating hematologists is valuable.
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Risk factors for developing acute chest syndrome include respiratory infections, treatment with opiates, and splinting due to chest or abdominal pain.
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