Sickle Cell Disease and Infection

1. Sickle Cell Disease and Infection Sherrill Brown, M.D. Assistant Clinical Professor Division of Infectious Diseases UC Davis Medical Center 9/8/18

2. Disclosures None

3. Goals for Discussion • Discuss the mechanisms that make Sickle Cell patients more susceptible to infections. • Review Common Infectious Complications in Sickle Cell Anemia • Diagnostic and Management Guidance for these Infections • Discuss Preventative Strategies

4. Infection is a major cause of morbidity and mortality for sickle cell patients. Worldwide, infections are the leading cause of death in sickle cell patients. In developed nations, such as the US, measures to prevent and effectively treat sickle cell disease and infection have led to a longer and better quality of life for our patients. Sickling of cells can be precipitated by many factors including dehydration, hypoxia, cold, dehydration as well as adhesion molecules and cytokines associated with infections.

5. Why are sickle cell patients more susceptible to infection? • Sickle Gene causing abnormal red blood cells causesan increased susceptibility to infection • Splenic Dysfunction • Acute and Chronic Inflammation and Ischemia Causing Organ Damage • Higher Risk for Healthcare Related Infections

6. Normal Splenic Function • Functions as a filter for damaged cells and micro-organisms in the blood. • Produces antibodies to fight infection. • Participates in complement activation. • Encapsulated bacteria are poorly opsonized by complement proteins and can only be effectively cleared by the spleen. • Streptococcus pneumoniae, Haemophilusinfluenzae, Neisseria meningitidis and Salmonella species

7. Splenic Dysfunction- 6mo to 3 yrs of age • The sluggish circulation through the spleen, high rates of O2 extraction and local acidosis promotes sickling which leads to blockage and diversion of blood through shunts. • Bypassing the normal filtering mechanisms. • Macrophages responsible for engulfing abnormal cells and microorganisms get blocked with sickled cells and cannot function properly. • Repeated episodes of this over time, leads to infarcts/death of spleen tissue.  Auto-splenectomy • Lack of IgM memory B cells • Cannot mount a rapid response to encapsulated organisms. • Overwhelming sepsis can develop quickly, especially in younger individuals.

8. Chronic end organ damage. • Bone marrow is expanded to create more RBCs, high O2 demand and blood flow is sluggish. • SicklingVaso-occlusion and Infarction of BoneDamaged bone at high risk of infectionOsteomyelitis • Patchy ischemia and infarction in bowel can lead to chronic intermittent translocation of gut bacteria. • Chronic microvascular disease is associated with increased risk for severe respiratory infection>Acute Chest Syndrome

9. Healthcare Associated Infections • Frequent transfusions with unsafe blood products in less regulated countries leads to increased risk of blood borne infection. • HIV, Hep B, Hep C, CMV, Parvovirus B19 • Frequent use of prolonged central catheters leads to increased risk of Central Line Associated Bloodstream Infection • Increased pain medication requirements respiratory depression and inactivitypneumonia, bed sores and ulcers, decreased cardiac stamina

10. Infections may also precipitate Vaso-occlusion. Increased neutrophil counts correlate with the severity of SCD. Patients with severe SCD have increased expression of leukocyte adhesion molecules suggesting a role for leukocytes in the vaso-occlusive process.

12. Encapsulated Bacteria • Streptococcus pneumoniae • Haemophilusinfluenzae • Neisseria meningitidis • Salmonella species • Dysfunctions in splenic sequestration of these bacteria lead to severe infections • Meningitis, Bacteremia, Pneumonia, Osteomyelitis

13. Osteomyelitis Necrotic and damaged bone is at risk of infection especially from Salmonella species.

14. Encapsulated Bacteria Diagnosis/Treatment • Diagnosis • Blood culture prior to antimicrobials • CSF studies and culture if suspicious for meningitis • Strep pneumoniae urine antigen • MRI and Bone biopsy with path and culture if evidence of osteomyelitis • Prompt Anti-bacterials directed at common pathogens

15. Encapsulated Bacteria Prevention Routine childhood immunizations including additional scheduled Streptococcus pneumoniae, Neisseria meningitidis vaccines Annual Flu shot Oral Penicillin prophylaxis twice daily for children 3months-5yrs Frequent handwashing Washing fruits/vegetables including lettuce thoroughly, avoid cross contamination of meats with food especially chicken and eggs. Cook meats thoroughly.

16. Vaccines • https://www.cdc.gov/vaccines/schedules/ • Haemophilusinfluenzae • Pneumococcal conjugate and polysaccharide • Meningococcal ACWY, B Vaccine • Important to protect from encapsulated bacteria. • Additional vaccine doses recommended for Pneumococcal and Meningococcal vaccines.

17. PROPS Trial 1986

18. Parvovirus B19 • Infectious Prior to Rash and usually transmitted through Respiratory Droplet route. • Usually mild and self-limiting infection. • Erythema infectiosum “Fifth disease”, “slapped cheeks” • Non-specific viral illness • Post infectious arthropathy • More severe infections. • Infects erythroid progenitor cells->temporary cessation of erythropoiesis->Pure red cell aplasia • In pregnancy, novel infection hydrops fetalis, stillbirth, and spontaneous abortion.

19. Parvovirus B19 and Sickle Cell Sickle patients with chronic anemia due to decreased RBC lifespan depending on increased erythropoiesis to maintain baseline Hemoglobin. Infection leads to cessation of erythropoiesis for 7-10 days Leads to aplastic crisis, severe anemia and vascular collapse in severe infection. Requires prompt identification, droplet isolation, blood transfusion until erythropoiesis can resume again. Transient aplastic crisis in 65-80% of infections in Sickle cell disease.

20. Parvovirus Diagnosis/Treatment Diagnosis: Parvovirus B19 IgM or Parvovirus PCR with clinical correlation Treatment: supportive care, blood transfusions in Aplastic crisis

21. Parvovirus Prevention No vaccine at this time. Infection leads to lifelong protection, and infection uncommon after age 15. Isolate infected or exposed individuals from other at risk populations (immune compromised, sickle cell patients) DROPLET precautions Wash hands frequently and avoid people with respiratory illnesses or rash

22. Acute Chest Syndrome (ACS) Chest pain, SOB, fever, pulmonary infiltrates on CXR Looks like a pneumonia Precipitants include: pulmonary infection, fat embolism from bone infarcts, decreased respiration. Sickling and vaso-occlusion in the lung lead to local ischemia and infarction.

23. ACS Diagnosis/Treatment • Attempt to identify underlying cause • Chest CT with contrast to eval for fat embolism • Respiratory viral panel, Flu testing, Streptococcus pneumoniae antigen, sputum culture if productive cough, MRSA nares screening • Supportive care and antimicrobials directed at possible infectious etiology • De-escalate antimicrobial therapy if alternative cause is identified.

24. ACS Prevention Optimize sickle cell treatment to avoid sickling episodes and end organ damage. Decrease respiratory depressant medications and encourage deep breathing with incentive spirometry. Get good ventilation and avoid sick contacts. Wash hands frequently. Get all routine vaccinations including annual flu shot, Strep pneumonia vaccines, Hemophilusinfluenzae vaccine.

25. Yersinia enterocolitica Gram negative coccobacilli Transmitted by Fecal Oral route through contaminated hands, food, water Causes diarrhea and can cause abdominal lymph node swelling and blood stream infection. “pseudo-appendicitis”, RLQ abdominal pain, rectal bleeding, ileal perforation. Can also cause pharyngitis and erythema nodosum. Disease more common in iron overload syndromes such as in Sickle Cell Disease. HLA-B27 a risk factor for reactive arthritis

26. Y. enterocoliticaDiagnosis/Treatment • Blood Culture • Stool Culture • Pharyngeal Culture • Lymph node biopsy • Treatment indicated in those that are severely ill. • Ciprofloxacin, TMP/SMX, or Doxycycline for about 5 days • Ceftriaxone + Genamicin in severe sepsis

27. Y. enterocolitica Prevention Eat food that has been prepared using hygienic precautions. Avoid raw or undercooked meat and seafood (tripe, chitterlings) Wash fruits and vegetables carefully. Drink purified water. Wash hands with soap and water. Screen blood bank donors for acute symptoms of infection.

28. Healthcare Associated Infections (HAIs) Hospital Acquired Pneumonia Central Line Associated Blood Stream Infections Catheter Associated Urinary Tract Infections Clostridium difficile Colitis Antibiotic Resistant Bacterial Infections Spread of Infections from Healthcare Workers or Patients to other Patients.

29. Hospital Acquired Pneumonia Pneumonia acquired and diagnosed 2 or more days after admission to a hospital. Higher risk of antibiotic resistant organisms as cause including MRSA or Pseudomonas. Necessitates broader spectrum antibiotics to start. Prolongs hospitalizations and increases risk of needing additional procedures.

30. Central Line Associated Bloodstream Infections Central lines often needed due to poor venous access, exchange transfusions, and long term IV therapy in sickle cell patients. Central lines include: ports, tunneled catheters, dialysis catheters and PICC lines The longer a central line is in place, the higher the risk of bloodstream infection developing. Can lead to repeat line procedures, endocarditis and seeding infection to additional organs in the body (brain, lungs, kidneys, bones) Requires initiation of broad spectrum antibiotics to treat.

31. Catheter Associated Urinary Tract Infection Urinary Tract Infection in the setting of Indwelling Urinary catheter The longer the catheter is used, the higher the risk of developing infection. May be caused by drug resistant bacteria. Can lead to pyelonephritis, blood stream infections and more severe illness.

32. Clostridium difficile Colitis Infectious Diarrhea infecting the colon caused by Clostridium difficile Usually acquired after antibiotics use and spread from person to person on hands and surfaces. Sickle cell patients at higher risk given increased risk for admission and antibiotics use.

33. Prevention of Infection at Home Avoid sick contacts. Clean and prepare food carefully to avoid contamination. Cook meats fully. Stay hydrated with water and low sugar low caffeine beverages. Get plenty of rest, avoid stress and eat healthy nutritious meals. Caretakers, families and patients must wash their hands frequently with soap and water. Take all prescribed medications regularly. Seek care quickly if patients develop fever >38.5 or respiratory symptoms.

34. Prevention of Infection in the Clinic • Optimize Sickle Cell therapy to avoid pain crisis requiring hospitalization. • Get recommended vaccines to avoid infection leading to hospitalization. • Annual flu shot • Prescribe and take Penicillin prophylaxis to avoid Invasive Pneumococcal Disease. • Consider vitamin including Zinc supplementation. • Counsel patients on compliance with prevention strategies. • Healthcare workers wash hands frequentlywith soap and water or alcohol solution. • Patients and families wash hands frequently while at clinic.

35. Prevention of Infection at the Hospital Avoid the use of central lines and indwelling Foley catheters to avoid infection. Minimize broad spectrum antibiotics use to avoid development of resistance. Healthcare workers, caretakers and patients wash hands frequently. Frequently utilize incentive spirometry to expand lungs and limit hypoventilation.

36. Barriers to Prevention of Infection • Decreased understanding from families, caretakers, patients and healthcare providers about the importance of prevention including: • Hand hygiene • Meticulous preparation of foods • Avoiding sick contacts • Compliance with taking prescribed medications and vaccinations. • Many families with sickle cell disease are from socioeconomic groups with decreased access to resources such as stable housing, nutritious food, and appropriate medical care including prescriptions.

37. Future directions in infection prevention, diagnosis and treatment. Further research for prevention strategies in developing countries that are cost effective and directed at endemic pathogens. (ex. malaria, parasitic infections) Validate biomarkers that can help determine if a bacterial infection is complicating an ACS picture or febrile syndrome. (ex. Procalcitonin) Curative treatments that eliminate the damage from sickle cell in the beginning.

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