Management is similar to vaso-occlusive crisis, with the addition of antibiotics (usually a quinolone or macrolide, since cell wall-deficient ["atypical"] bacteria are thought to contribute to the syndrome), oxygen supplementation for hypoxia, and close observation. Should the pulmonary infiltrate worsen or the oxygen requirements increase, simple blood transfusion or exchange transfusion is indicated. The latter involves the exchange of a significant portion of the person's red cell mass for normal red cells, which decreases the percent of haemoglobin S in the patient's blood. The patient with suspected acute chest syndrome should be admitted to the hospital with worsening A-a gradient an indication for ICU admission.

Most people with sickle-cell disease have intensely painful episodes called vaso-occlusive crises. However, the frequency, severity, and duration of these crises vary tremendously. Painful crises are treated symptomatically with pain medications; pain management requires opioid administration at regular intervals until the crisis has settled. For milder crises, a subgroup of patients manage on NSAIDs (such as diclofenac or naproxen). For more severe crises, most patients require inpatient management for intravenous opioids; patient-controlled analgesia (PCA) devices are commonly used in this setting. Diphenhydramine is also an effective agent that doctors frequently prescribe to help control itching associated with the use of opioids.

Reticulocytopenia, also known as an "aplastic crisis" or "marrow failure", is the medical term for an abnormal decrease of reticulocytes in the body. Reticulocytes are immature red blood cells. Reticulocytopenia may be a result of viral parvovirus B19 infection, which invades and destroys red blood cell precursors and halts the red cell production. If infection occurs in individuals with sickle cell anemia, spherocytosis, or Beta thalassemia that will lead to incorporation of two anemia-induced mechanisms: decreased red cell production and hemolysis. The result is a rapid and severe anemia (aplastic crisis) which may require blood transfusion.