IGRT in SID

Immune Globulin Replacement Therapy (IGRT) in Secondary Immune Deficiency

*Background: IGRT is the accepted treatment of choice in the management of (humoral) primary immune deficiency syndromes. Evidence and clinical practice guidelines for IGRT in secondary immune deficiency (SID) syndromes is less well established but evolving. IGRT can be achieved with intravenous immune globulin (IVIG) or subcutaneous immune globulin (SCIG).

IGRT in SID

IVIG vs SCIG

Benefits of IVIG

  • Administration by health care professional under supervision avoids potential patient dexterity issues with self-administration and aids adverse reaction follow-up
  • Less burden on blood bank or pharmacy tech time preparing product for issue

Benefits of SCIG

Pregnancy in SCD

Pregnancy Complications in Sickle Cell Disease

*Summary: patients with sickle cell disease (SCD) have a higher risk of typical pregnancy complications than those without SCD in addition to complications related to the underlying pathophysiology of the disease.

Pathophysiology

Cardiovascular, respiratory, hematologic, and endocrine adaptations that normally occur in pregnancy may be particularly challenging in women with SCD. For example, cardiovascular output and total blood volume (primarily plasma volume) normally increase in the first trimester but this can exacerbate cardiovascular stress on a background of chronic organ and vascular damage. Additionally, physiologic respiratory system changes due to progesterone and an enlarging uterus, coupled with increased oxygen demands of the fetus, exacerbate anemia and intraerythrocytic sickling and endothelial dysfunction.

Placental function may be impacted by red cell sickling, endothelial damage, vascular occlusion, and inflammation, which, in conjunction with anemia, may impact fetal growth. Fetal growth and risk of preterm birth is further limited by the increased risk of preeclampsia.

Pregnancy Complications Exacerbated by SCD

Prothrombotic state in SCD and Pregnancy

  • Increased cellular adhesion & viscosity exacerbate venous thromboembolism risk in SCD patients 1.7-10x general population
  • Prevention:
    • Peri-partum: compression stockings & lmwh prophylaxis during hospitalizations
    • Post-partum: depomedroxyprogesterone acetate may reduce painful crises and improve hematological parameters

Preeclampsia

  • 2.42x relative risk compared to general population and even higher in SCD patients with concomitant HIV; thought to be related to chronic inflammation in SCD
  • Prevention: same as general population - low dose aspirin from 12 weeks gestation

Maternal Mortality

  • 18x reative risk of death due to acute coronary syndrome, stroke, hemorrhage, and venous thromboembolism

SCD Complications Exacerbated by Pregnancy

(Hyper)hemolytic Reactions

  • Increased risk of acute hemolytic transfusion reaction, delayed hemolytic transfusion reaction, and hyperhemolysis (especially if pre-existing alloantibodies) thought to be due to complement upregulation in pregnancy
  • Prevention: avoid transfusion (alternatives: EPO and IV iron) but if unavoidable, prospectively antigen match
  • Treatment: IVIG, steroids, eculizumab, rituximab

Vaso-occlusive Pain

  • +/- exacerbated by pregnancy; experienced by ~50% of pregnant SCD patients (28.5% during labor & delivery)
  • Prevention: incentive spirometry, ambulation, +/- thromboprophylaxis
  • Treatment: analgesics

Retinopathy

  • Thrombosis of vessels in the retina and choroid results in abnormal blood flow and retinal thinning
  • Prevention: screening since SCD retinopathy can be exacerbated by pregnancy and pregnancy-related complications (gestational diabetes)

Cerebral Infarcts

  • Stroke prevalence in SCD: 3.75%; pathophysiology related to hypercoagulable state in SCD, exacerbated by hypercoagulability of pregnancy &/or hypertension-related complications, increasing risk of ischemic and hemorrhagic strokes, respectively

Liver Infarcts

  • “Sickle cell hepatopathy” due to intrahepatic sickling during a sickle cell crisis leads to ischemia, sequestration, and cholestasis causing transaminitis (resolves within ~2 weeks)
  • Treatment: rehydration & oxygenation

Medication Changes

Discussion of the risks and benefits of the following medications during pregnany should be personalized for each pregnant patient with SCD dependent on their complication & risk profile:

Complications of SCD in Pregnancy on the Fetus

Spontaneous Abortions

  • Increased perinatal mortality: 1.6 stillbirths/1000 deliveries (Canada) up to 5x higher than general population in lower resource countries

Restricted Fetal Growth

  • Placental insufficiency due to vascular occlusion & endothelial damage, as well as, lower BMI in pregnant women with SCD increases the risk for IUGR (5x > RR), low birth weight, small for gestational age (28-45% liveborn), and prematurity (2x > RR)
  • Complications: neurodevelopmental delay, poor school performance, metabolic disease, and obesity

SCD Inheritance

  • Autosomal recessive pattern
  • Offspring of 2 carriers (+/- affected) have a 25% chance of inheriting SCD, 50% chance of being a SCD carrier, and 25% chance of not having or carrying SCD

Transfusion Considerations for Pregnant SCD Patients

Transfusion Thresholds

  • BCSH guidelines part 1 and 2 offer recommendations for transfusing pregnant patients with SCD (below), however, transfusion of patients with SCD is highly personalized/individualized based on their clinical and transfusion history and should be overseen by an expert
    • Simple or exchange transfusion for SCD complications or high maternal or fetal risk & simple transfusion for severe anemia
    • Safe hemoglobin threshold for lab to screen RBC transfusion orders for pregnant SCD patients: 50 g/dL

Product Selection

  • International Collaboration for Transfusion Medicine Guidelines (ICTMG) recommendations:
  • For patients without alloantibodies, to reduce the risk of alloimmunization, ABO, D, CcEe, K-matched RBCs are recommended (low quality evidence, weak recommendation)
  • For patients with clinically significant alloantibody(ies), RBCs antigen negative to the alloantibody present are recommended (low quality evidence, strong recommendation) and CcEe K Fya Fyb Jka Jkb S s-matched RBCs should probably be transfused (low quality evidence, weak recommendation) to reduce the risk of further alloimmunization
  • Attention! Limited availability of extended phenotype-matched units should NOT delay transfusion such that it would adversely affect patient care

Future SCD Cure?

CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia

  • CRISPR is a tool that employs programmable RNA-guided DNA targeted by Cas9 to edit genes
  • This tool has been harnessed to effectively cure some hemoglobinopathies by neutralizing Bcl11a (which mediates the repression of γ-globin, a component of HbF) in autologously collected bone marrow for transplant post-conditioning, resulting in hematopoietic cells that produce HbF rather than defective HbA
  • Preclinical data demonstrated increased HbF as a percentage of total hemoglobin after edited cells were differentiated into erythroid cells
  • Preliminary (human) trial data showed successful transplantation of patients with SCD and transfusion-dependent β-Thalassemia using autologous stem cells treated with CRISPR (transfusion independent at 1 year)

COVID-19 & Pregnancy

COVID-19 Updates RE: Pregnancy

I have a lot pregnant friends and family members right now so Archives' latest slew of articles on the effects of COVID-19 on pregnant women and their infants particularly piqued my interest. Here are a few poignant pearls I took away:

Coronaviruses in Pregnancy - Analysis of 38 women with COVID-19 and review of prior coronaviruses' impacts on pregnancy

SARS-CoV1

  • 25% fatality rate in pregnant women
  • Complications to fetus: miscarriage, intrauterine growth restriction, preterm birth
  • No vertical transmission

MERS

  • Maternal deaths
  • Complications to fetus: perinatal deaths, intensive care treatment for newborns, and prematue deliveries
  • No vertical transmission

SARS-CoV2

  • No maternal deaths
  • Complications to fetus: small & large for gestational age, fetal demise, dyspnea, bacterial pneumonia
  • No vertical tranmission
  • Virus NOT identified in amniotic fluid, breast milk, umbilical cord blood, or fetal throat swabs

Respiratory Viruses RARELY, if ever, are transmitted vertically to the fetus

  • The absence of reports of maternal-fetal transmission of the SARS-CoV2 virus during the COVID-19 pandemic is similar to other coronaviruses, and consistent with the extreme rarity of intrauterine transmission of other respiratory RNA viruses
  • Few confirmed or suspected cases of vertical transmission of: influenza and RSV
  • No reported cases of vertical transmission of: parainfluenza virus and human metapneumovirus

Why?

  • Placental membranes lack mRNA to manufacture ACE2 receptor and TMPRSS2 used by SARS-CoV2 to enter cells
  • In contrast, placentas contain large amounts of the proteins that allow Zika virus & CMV to enter cells and have demonstrated vertical transmissibility, according to an NIH study

Contrdictory finding in placental study series: rare case of vertically transmitted SARS-CoV2

Histological Findings in the Placenta