The manifestation of sickle cell disease usually occurs in early childhood. The most common symptom of SCD is sickle cell crisis. It occurs due to obstruction of blood circulation in microvascular bed by the sickled erythrocytes, resulting in ischemic injury to the affected tissues. 

Pain crisis is the most important clinical feature of SCD and responsible for highest numbers of hospital admissions among SCD patients. Nearly 50% of the patients suffer from pain crisis. A sickle cell crisis is frequently associated with fever, malaise and leukocytosis. 

The pain crisis usually starts abruptly. The duration of crisis may last between several hours and several days and again terminates as abruptly as it begins. Bone marrow infraction due to vaso-occlusion often causes bone pain. As the bone marrow activity has defined patterns in different age groups, the pain also follows those patterns. For example, in children aged less than 18 months, metatarsal and metacarpals are involved, presenting as dactylitis. As age increases, the pain tends to occur in the extremities of long bones. It may resemble as joint pain due to proximity to the joints as well as sympathetic effusion. During adolescence, the pain moves towards the vertebral bodies, mainly the lumber ones. Though these patterns are common presentation of pain crisis, there might be other pain presentations depending on the affected site. Pain affecting the long bones is usually bilateral and symmetrical. Recurrent episodes in same individual usually follow the same distribution [2] [3] [10].

Involvement of the abdomen may present as acute abdomen case [8]. Acute abdomen may occur due to infraction of intra-abdominal organs or referred pain from other sites. Abdominal pain may be accompanied by back or joint pain. Vomiting is also a common presentation of such abdominal pain [2] [3] [9]. Each pain crisis episode generally involves two or more sites.  

Repeated episodes in the spleen leads to infractions and auto-splenectomy which may predispose to life-threatening infections. The liver may also suffer from infarction leading to hepatic failure. Renal involvement causes papillary necrosis which causes isosthenuria (i.e. inability in concentrating urine).

• Fatigue

  Other symptoms that developed included fatigue, left-sided rib pain, and shortness of breath. The patient recalled being told that she had sickle cell trait but said that she never had a sickle cell crisis. [ncbi.nlm.nih.gov]

  What treatments manage symptoms of fatigue and anemia? Fatigue is a common symptom in persons with sickle cell anemia. Sickle cell anemia causes a chronic form of anemia, which can lead to fatigue. [medicinenet.com]

  This is a gradual process, characterised by an insidious onset of fatigue over several days, as well as fever and malar rash ("slapped cheek") The characteristic feature is reticulocytopenia: the reticulocyte count is usually very low. [derangedphysiology.com]

• Pallor

  General sickle crisis management Assessment History Symptoms and duration of pain, dyspnoea, fever, pallor and lethargy Provoking factors (fever, travel, procedures, recent hospital admission) Past history of chest crises and management - ICU admission [rch.org.au]

  Pallor. First aid treatment for a sickle cell crisis Provide reassurance Contact medical help -> the patient may know the details of who to contact during a crisis. [firstaidforfree.com]

  C) Difficulty breathing Chest pain Seizure Severe headaches Swelling in the abdomen (belly) Sudden weakness Weakness on one side of the body Loss of feeling and movement A painful erection of the penis lasting more than 4 hours Pallor When to call your [mountnittany.org]

  Anaemia, jaundice, pallor, lethargy, growth restriction and general weakness; the most common causes of anaemia are acute splenic sequestration, transient red cell aplasia, and hyperhaemolysis in patients with severe infection.[3] Increased susceptibility [patient.info]

• Intravenous Administration

  The requirement for intravenous administration limits the use of the agent. However, many drugs now are administered intravenously to patients at home (e.g., desferrioxamine for iron overload). [sickle.bwh.harvard.edu]

• Limb Pain

  The major symptoms are anemia, periodic joint and limb pain and sometimes edema of the joints, chronic ulceration about the ankles, episodes of severe abdominal pain with vomiting, and abdominal distention. [medical-dictionary.thefreedictionary.com]

• Pneumonia

  Pneumocystis carinii pneumonia (PCP) usually occurs in the setting of preexisting immunosuppression. We present a case of PCP that occurred in an HIV-negative woman with severe sickle cell disease. [ncbi.nlm.nih.gov]

  Both adults and children are at risk for a variety of infections, such as pneumonia and bone infections. They should be examined whenever they experience fevers, since early diagnosis and treatment result in better outcomes. [medlineplus.gov]

  […] paracetamol, +/- NSAIDs, opiates — rehydrate with oral or IV fluids according to severity of pain — chronic pain may be an issue acute chest syndrome — O2 and aggressive pain management (prevent hypoventilation) — consider empiric antibiotics in case of pneumonia [lifeinthefastlane.com]

• Abdominal Pain

  Abdominal pain is quite common in sickle cell crisis, although the cause of abdominal pain is seldom determined and remains controversial. [ncbi.nlm.nih.gov]

  Other types of vaso-occlusive crisis in sickle cell anemia include dactylitis, priapism, abdominal pain, and jaundice. 1)Full blood count to check for Hemoglobin levels and 2) Rapid diagnostic test (RDT) for Malaria to be able to rule out malaria in the [en.wikipedia.org]

• Acute Abdomen

  Involvement of the abdomen may present as acute abdomen case. Acute abdomen may occur due to infraction of intra-abdominal organs or referred pain from other sites. Abdominal pain may be accompanied by back or joint pain. [symptoma.com]

  As an example, patients presenitng with abdominal painful crisis can mimic acute abdomen and the differential should include condidtions that give acute abdominal pain such as, Acute Appendicitis, acute Pancreatitis, acute pyelnephritis, Pelvic inflammatory [ncbi.nlm.nih.gov]

• Severe Abdominal Pain

  Abdominal crisis: The pain associated with the abdominal crisis of sickle cell disease is constant and sudden. It becomes unrelenting. The pain may or may not be localized to any one area of the abdomen. [emedicinehealth.com]

  Severe abdominal pain may develop with or without vomiting and is usually accompanied by back and joint pain. Acute chest syndrome is characterized by sudden onset of fever, chest pain, and pulmonary infiltrates. It may follow bacterial pneumonia. [merckmanuals.com]

  The major symptoms are anemia, periodic joint and limb pain and sometimes edema of the joints, chronic ulceration about the ankles, episodes of severe abdominal pain with vomiting, and abdominal distention. [medical-dictionary.thefreedictionary.com]

  Other serious warning signs that signal a need for immediate medical treatment are: Pain that doesn’t go away with home treatment Severe abdominal pain (stomachache) or swollen belly Chest pain Sudden vision problems Headache that’s different from usual [med.umich.edu]

• Right Upper Quadrant Pain

  Also Case 1 had an episode of right upper quadrant pain due to vaso-occlusion and acute sequestration of RBCs in the hepatic sinusoids, which is called ‘Right Upper Quadrant Syndrome’. [ncbi.nlm.nih.gov]

• Chest Pain

  […] syndrome, osteomyelitis, local or systemic infection vaso-occlusive crisis — assume this is the cause of any painful presentations acute chest syndrome — life-threatening lung infarction — assume if hypoxia + chest pain acute splenic sequestration — [lifeinthefastlane.com]

  Chest pain and hypoxaemia may be the only signs. Chest pain should be treated as an acute chest syndrome and not simply as a vaso-occlusive crisis. [rch.org.au]

  38.5 C (101.3 F) New pulmonary infiltrate on chest x-ray Respiratory symptoms (coughing, wheezing, or shortness of breath) Hypoxemia Therefore, the evaluation of chest pain in patients with SCD should always include a chest x-ray. [emlyceum.com]

• Heart Murmur

  The heart usually enlarges, and an enlarged heart is less effective in pumping blood to the body, possibly leading to heart failure. Heart murmurs are common. [merckmanuals.com]

• Hip Pain

  pain for the past two years. [orthobullets.com]

  Painful vaso-occlusive crisis causes severe pain in long bones, the hands and feet, back, and joints. Hip pain may result from avascular necrosis of the femoral head. [merckmanuals.com]

  If avascular necrosis of the hip is suspected in a patient with hip pain and difficulty in walking, consult an orthopedist for possible hip joint replacement. Orthopedic consultation is also appropriate if osteomyelitis is suspected. [emedicine.medscape.com]

• Arthralgia

  Adverse effects experienced with this new agent included arthralgia, diarrhea, pruritus, vomiting, and chest pain.24 This new agent has promising results, and further studies are warranted to further evaluate its utility. [uspharmacist.com]

• Aggressive Behavior

  Neuropsychiatr 22: 38–41 PubMed Google Scholar Mauceri L, Sorge G, Baieli S et al. (2000) Aggressive behavior in patients with Sotos syndrome. [link.springer.com]

• Hematuria

  Unilateral hematuria (by unknown mechanisms and usually from the left kidney) can occur but is self-limited. [merckmanuals.com]

  Other problems associated with vasoocclusion include priapism, hematuria, and retinopathy. Anemic crisis is characterized by a dramatic, rapid drop in hemoglobin levels resulting from various causes. [medical-dictionary.thefreedictionary.com]

  Microscopic hematuria is a common problem in patients with sickle cell disease (as well as some patients with sickle cell trait). Hematuria per se requires no intervention unless blood loss is massive. [sickle.bwh.harvard.edu]

• Stroke

  Patients with sickle cell disease may present with the following problems Vaso-occlusive crisis Fever Acute chest syndrome Acute splenic sequestration Aplastic crisis Stroke Priapism Many of these presentations require urgent treatment, and discussion [rch.org.au]

  […] sequestration — typically occurs in infants — associated with increased spleen size — fall in Hb by >20 g/L, thrombocytopenia but normal or increased reticulocytes aplastic crisis — fall in Hb as well as reticulocytes — triggered by parvovirus infection stroke [lifeinthefastlane.com]

  […] regardless of the dominant presentation symptoms and signs of local and systemic infection respiratory signs and symptoms increasing spleen size shock and evidence of organ failure baseline and current Hb CXR if fever, chest pain or hypoxia CT Head if stroke [litfl.com]

  […] may suffer a clinical stroke by age 45. [nhlbi.nih.gov]

  The patient’s risk of stroke should be established with a transcranial doppler scan to measure blood flow in the brain as a risk factor for stroke. [news-medical.net]

• Somnolence

  The analgesics should not be discontinued automatically for somnolence as long as the patient is easily aroused. A common misconception is that if a person is sleeping, the analgesics are controlling the pain. [sickle.bwh.harvard.edu]

• Asthenia

  […] nivelissä English pain in the back, arms, legs, shoulders, bones, joints Last Update: 2017-04-26 Usage Frequency: 1 Quality: Finnish - kipu lihaksissa ja luissa, huonovointisuus (astenia) tai kuume English - pains in your muscles and bones, feeling unwell (asthenia [mymemory.translated.net]

The investigation of a patient with vaso-occlusive crisis should include a complete medical history, physical examination, selected laboratory workups and searching for precipitating factors which initiate the crises. The clinicians must examine for clinical evidence of associated infection and dehydration. The extent to which bone and soft tissues are affected should also be scrutinized. 

In patients with severe symptoms the laboratory tests should include complete blood count, urine analysis and reticulocyte count. If the patient is presented with fever, then an X-ray chest should be carried out along with culture of urine, sputum and blood to find out the possible source of infection. However, fever is a common symptom even in patients with uncomplicated vaso-occlusive crisis and therefore fever does not always indicate the presence of associated infection [3]. Painful crisis without bone marrow aplasia usually have increased count of white blood cells, often shifting to the left. This scenario is particularly found in case of bacterial infection. Platelet count also tends to increase.

In patients presenting with chest pain and/or difficulty in breathing, an acute chest syndrome or pulmonary embolism should be considered; hence chest radiograph and pulse oximetry are needed to exclude these differential diagnosis. 

• Neutropenia

  […] dehydration hypoxia drugs (e.g. sedatives, local anaesthetics) Patients with sickle cell disease are at risk of infection due to underlying immunosuppression functional aspleina typically develops in childhood prophylactic treatment with hydroxyurea can cause neutropenia [lifeinthefastlane.com]

  ICD-10-CM Diagnosis Code R50.81 Fever presenting with conditions classified elsewhere 2016 2017 2018 2019 Billable/Specific Code Manifestation Code Code First underlying condition when associated fever is present, such as with: leukemia ( C91 - C95 ) neutropenia [icd10data.com]

• Reticulocytosis

  However, they had pronounced reticulocytosis, polychromasia, and increased nucleated red blood cells beyond their steady state levels. Diggs7 noted a similar picture in one of his patients. [adc.bmj.com]

  As discussed, sickle cell patients maintain a baseline hemoglobin level of approximately 7-10mg/dL and a compensatory reticulocytosis between 5-10%. [emlyceum.com]

  Nucleated RBCs frequently appear in the peripheral blood, and reticulocytosis ≥ 10% is common. Dry-stained smears may show sickled RBCs (crescent-shaped, often with elongated or pointed ends). [merckmanuals.com]

  Hyperhemolytic crisis, characterized by anemia, jaundice, and reticulocytosis, results from glucose-6-phosphate dehydrogenase deficiency or occurs as a reaction to multiple transfusions. [medical-dictionary.thefreedictionary.com]

  Assessment and Diagnostic Findings The patient with sickle cell anemia usually has the following laboratory results: CBC: Reticulocytosis (count may vary from 30%–50%); leukocytosis (especially in vaso-occlusive crisis), with counts over 20,000 indicate [nurseslabs.com]

• Heinz Bodies

  None of these patients presented with the classical “coca-cola” coloured urine or presence of Heinz bodies on reticulocyte preparations that are so characteristic of this condition. [adc.bmj.com]

• Liver Biopsy

  Transjugular liver biopsy showed focal areas of confluent necrosis and large areas of collapse. Cocaine intoxication should be considered in the differential diagnosis of hepatic failure in patients with sickle cell anemia. [ncbi.nlm.nih.gov]

Most pain related to sickle cell disease can be treated with usual pain medications such as aspirin and ibuprofen. These can be found over the counter. In case of severe pain opioid (i.e. morphine) drugs  can be used along with routine pain medications. Some patients may be need hospital admission for severe pain.

 Acute pain crises are usually managed with drug therapy. Opioids like morphine are the drug of choice for such acute pain management. If necessary, paracetamol and NSAIDs can be used alongside opioids. Psychological support is very important in this regard. The standard treatment protocol includes opioid analgesics, rest, maintaining adequate hydration and cognitive-behavioral therapy [2]. There are several effective drug regimens for the treatment of pain crisis in SCD. Pain crisis management should follow the  “analgesic ladder” - a three step ladder approach recommended by the World Health Organization (WHO) for treating cancer-related pains [11].The choice of analgesic and the dosage schedule should  be based on pain severity and location.

Patients suffering from mild  pain can be treated at home by prescribing non-narcotic analgesics and oral fluid therapy [2] [12]. Acetaminophen can also be prescribed depending on the severity of pain. Non-steroidal anti-inflammatory drugs (NSAIDs) can also be used unless there are specific contraindications such as peptic ulcer disease (PUD), renal insufficiency or hepatic dysfunction.

Patients suffering from moderate to severe pain can be treated with narcotic analgesics. Effective pain management can be achieved through titration of dosage of the narcotic analgesics [1][2][12]. Usually morphine is given intravenously on hourly basis. Once the effective pain management occurs, then 3 hourly. Usually oral morphine is used in sustained release form after 24-48 hours after the pain is controlled. 

Severe pain episodes require emergency hospitalization. Stronger opioid analgesics are the drug of choice [6] [1] [2] [12] [13]. Though there are inconclusive findings about the efficacy of oxygen therapy in vaso-occlusive episodes, it is often used in managing such patients [13] [14].

Sickle cell crisis is often treated with adequate intravenous fluid administration and analgesics. Intravenous fluid management should be sufficient to correct ongoing dehydration and to replace fluid losses due to insensible loss and  fever. Usually normal saline and 5% DNS (i.e. dextrose in saline) are used to correct fluid balance. Dehydration may increase the plasma osmolarity and thus can worsen vaso-occlusive crisis through hemoglobin polymerization, intra-cellular dehydration and further sickling. The goal of fluid management is to maintian an euvolemic state.

In mild vaso-occlusive episodes, oral rehydration can be used. Parenteral administration is indicated in patients with vomiting, volume depletion and severe pain. In such cases, when existing volume deficits are corrected with normal saline, 5 percent DW (i.e. dextrose in water) or  25 percent normal saline [15]. In painful crises intravenous morphine is effective and safe; however meperidine is avoided.

Being a lifelong disease the prognosis of SCD is usually guarded. The main aim of management is to achieve a normal life span with minimal morbidity. Prognosis improves as the therapy improves. Aseptic necrosis may occur especially in weight bearing axis (e.g. femur) due to repeated infraction of bones, joints and growth plates. Such complication might lead to chronic disability requiring changes in lifestyle and employment. The economic loss and burden of disease soar up with such chronic pain. The frequency and duration of crisis, affected regions of the body and pain intensity affects patient's life quality [1]. 

The prediction of vaso-occlusive crisis in sickle cell disease is quite difficult. In many patients, the exact cause of this crisis cannot be determined. However, dehydration, infection and cold weather are the common precipitating factors [1].

Factors that possibly cause sickle cell crisis:

• Cold weather 
• Infections
• Low oxygen tension
• Dehydration 
• Extreme physical exercise 
• Concomitant clinical conditions i.e. sarcoidosis, diabetes mellitus, herpes etc. 
• Acidosis 
• Alcohol consumption
• Pregnancy

Sickle cell disease is a common problem in black population. The condition is also quite prevalent in the Middle East and Eastern Mediterranean regions. The estimated prevalence of sickle cell trait (i.e. heterozygous) is up to 30% in some parts of African region. SCD is also found in malaria endemic areas e.g. some parts of Greece, Sicily, southern Turkey and India. Epidemiological data has shown that around 5.2% of patients with sickle cell disease have 3 to 10 severe pain episodes every year [4], which usually resolve within 5 to 7 days in most of the patients. Though pain in severe episode may persists for weeks to months [1]. Patients with sickle beta 0-thalassemia and homozygous SCD suffer more from vaso-occlusive pain than patients with sickle beta(+)-thalassemia and hemoglobin SC [4] [5].

Pain is the commonest complication of SCD. While travelling through the small blood vessels, the sickle cells obstruct small vessels, thereby hampering the blood flow. This results in sudden pain which can be mild to severe in nature and can last for different lengths of time. Acute exacerbation can occur intermittently; often for unknown causes. In some cases, viral infection, fever or local injury can precipitate the sickle cell crisis. 

Sickle cell crisis is mainly caused by ischemia and infraction of the affected area. Typically it occurs in the bones. Moreover, spleen, kidneys or lungs can be affected to a lesser extent. The crisis is initiated and maintained through the interactions among sickle cells, plasma constituents and endothelial cells  [6]. Occlusion of micro-vascular beds by sickle erythrocytes causes ischemic injury in the affected tissues. Occlusion of blood flow results in regional tissue hypoxemia and acidosis which leads to recurrent tissue injury and pain.  

On the other hand, chronic pain occurs due to destruction of bone tissues, joints and visceral organs as a consequence of recurrent injury done by crises. The unique pain syndrome occurs when unpredictable acute pain occurs on top of chronic pain [1] [7]. Severe pain symptom is probably resulting from increased intra-medullary pressure in the long bones, especially around the juxta-articular areas. This occurs as a result of acute inflammation and vascular necrosis of bone marrow tissue [3]. The pain originates from the involvement of periosteum or peri-articular soft tissues around the bone joints. 

To prevent vaso-occlusive crises, patients should be aware of the precipitating factors for it. That's why patient education to recognize early signs of crisis is the cornerstone of prevention. Patients should seek help from the physician in case of fever or other imminent illness causing the crisis. Family members should also be educated on patient care such as hydration, diet, medication and immunization. Patients with SCD are susceptible to dehydration as they have decreased ability to conserve water. This occurs due to inability of kidneys to concentrate urine. Therefore, the patients should be advised to drink adequate water in hot weather and avoiding exercise at the point of eminent fatigue and dehydration. Patients are also advised to wear proper clothes depending on the environment to maintain normal core temperature. Regular follow up with blood counts should be carried out. Genetic counselling and testing is required for the patients as wells as asymptomatic heterozygous carriers. 

Vaso-occlusion in sickle cell disease (SCD) is responsible for wide variety of clinical complications such as sickle cell crisis, leg ulcers, stroke, renal insufficiency and spontaneous abortion. Among them, sickle cell crisis is the commonest one and is the main reason for emergency consultation in patients with SCD. Nearly half of the homozygous SCD patients suffer from vaso-occlusive crisis. However, its frequency is highly variable. 

Sickle cell disease (SCD) is a common inherited disease worldwide. Sickle cell crisis is the most common complication of SCD. Though in most patients, cause of this crisis is unknown, a number of factors can precipitate this condition such as infection, cold weather and dehydration [1]. The pain episodes are sudden in onset and gnawing and throbbing in nature. The skin of the affected region might be tender, warm, red and swollen. Recognizing pain crisis symptoms early and minimizing the precipitating factors are necessary to prevent such crisis. Patients are usually managed with adequate fluid management and transfusion of hemoglobin to decrease the level of hemoglobin S. The pain management is done by NSAIDs and opioid drugs. Family physician along with a hematologist should manage the patient to alleviate pain and prevent future crisis.

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