Learning Lessons About Hemoglobin SC Disease From the Dengue Pandemic

Sickle cell disease (SCD) is known for its propensity to cause excruciating acute pain from vaso-occlusion (VOC), often requiring acute care and parenteral opioids, and profoundly impacting quality of life. Traditionally, patients with the hemoglobin (Hgb) SS genotype experience more profound complications with pain crises occurring early in life. Patients with Hgb SC are expected to have a milder phenotype with less frequent VOC, often delayed by several decades. Inflammation commonly triggers the pathophysiological processes that result in VOC. This inflammation can be from viral or bacterial infections, red cell dehydration–induced erythrocyte sickling, hemolysis, and free heme–induced oxidant stress.¹  We still have much to learn about how various acute infections may lead to a profound inflammatory response and the downstream acute and chronic complications in SCD, and how this varies by type of infection and genotype.

Dengue is a tropical, mosquito-borne viral infection endemic to more than 100 countries worldwide. Endemic dengue overlaps closely with the epidemiology of SCD. Dengue infection causes a rapid increase in inflammatory cytokines and various mediators that result in endothelial damage, increased vascular permeability, and plasma leakage with aberrations to both hemodynamics and coagulopathy.^2,3  In a recent retrospective cohort study, investigators Dr. Narcisse Elenga and colleagues studied the risk factors for severity of dengue infection among hospitalized children with SCD in the tropical countries of the French Americas. This study was conducted in an eight-year period between 2005 and 2013 in Martinique and Guadeloupe, and in French Guiana in 2013 during epidemic outbreaks of dengue not unlike the current global COVID-19 pandemic. Some important lessons learned from this study may shed light to our understanding of how to approach the nuanced management of SCD in the COVID-19 pandemic.

Participants were aged 15 years and younger with no prior history of dengue fever, and the cohort included 106 hospitalization events spread across three genotypes: 35 SS, 35 SC, and 36 individuals without SCD or any other chronic illness. Investigators used predetermined criteria to define severe and non-severe dengue infection. Among the participants with SCD, the median age was eight years; there were 30 males and 40 females. The control group patients had a median age of one year with 20 male and 16 female patients. In a surprise finding, results showed that compared to those with Hgb SS and compared to control subjects, participants with Hgb SC were more likely to develop multiorgan failure, acute pulmonary complications, require level 3 analgesic treatment for pain, and be more likely to develop a more severe form of dengue (Table).

Multiple logistic regression analysis demonstrated that having Hgb SC genotype, acute pulmonary complications, and multi organ failure was significantly associated with having severe dengue. This contrasts starkly with the current thought that individuals (particularly children) with Hgb SC genotype have a less severe disease.

It remains unclear why Hgb SC was over-represented among the severe dengue group with regards to mortality and severity of complications. Authors also describe differences in clinical presentation of dengue infection between genotypes with acute anemia being the main presentation in Hgb SS. While both genotypes presented with acute VOC pain, Hgb SC tended to have a higher pain intensity requiring escalation to level 3 analgesia compared to Hgb SS.

The molecular basis of Hgb C differs from that of Hgb S. In Hgb S, the point mutation of GAG to GTG replaces glutamine acid for valine on the β globin chain [β6 Glu → Val] and Hgb polymers form that lead to red cell sickling. With Hgb C there is a point mutation of GAG to AAG that replaces the glutamic acid for lysine in the β globin chain [β6 Glu → Lys]. This mutation results in the propensity for red cell dehydration; as the intra-erythrocyte contents become denser, there is increased tendency to formation of crystals instead of long hemoglobin polymers. Historically, Hgb SC has been thought of as a milder form of SCD, but emerging evidence suggests this may not be universally true. A recent cross-sectional study⁴  of children with SCD that included 111 with Hgb SS and 49 with Hgb SC showed no statistically significant differences in absolute neutrophil count (ANC), serum ferritin, or γ glutamyl transferase (GGT) between HGB SS and Hgb SC, with the expected differences in markers of hemolysis. Serum α 1 antitrypsin (AAT) levels as a marker of inflammation were also no different between the two genotypes.⁴  Additionally, there were no statistically significant differences between genotypes in frequency of infections, pneumonia, splenomegaly, or bone alternations. Put together, although Hgb SS presents acutely at an earlier age with more severe aberrations to laboratory profiles for hemolysis and inflammation, individuals with Hgb SC remain at risk of poor outcomes, particularly if their disease and subtle clinical and laboratory differences are ignored.

There are several reports of more severe consequences and complications (acute chest syndrome, multiorgan failure, requirement of intensive care support) from infections among Hgb SC for parvovirus B19, which results in fat emboli syndrome from extensive bone marrow necrosis.⁵  In addition, a study by Dr. Angela Rankine-Mullings and colleagues, the unadjusted odds of dying from severe dengue infection were higher for those with Hgb SC disease compared to homozygous SS disease with an overall response of 4.4 (95% CI, 0.6 - 31.7).⁶  Various hypotheses for why Hgb SC may be at increased risk from various viral and other infections include increased propensity for inflammatory mediated red cell dehydration and intracellular crystal formation that increases blood viscosity in Hgb SC, thereby compromising downstream tissue perfusion. However, further studies are needed to fully elucidate these mechanisms.

As we face the global viral pandemic of COVID-19, the emerging literature raises additional concerns about the risk of poor outcomes among individuals with Hgb SC. Dr. Julie Panepinto and colleagues recently reported early findings from the SECURE SCD COVID-19 registry (www.covidsicklecell.org/) that demonstrated a higher risk for severe COVID-19 disease course in SCD and a high case-fatality rate in a relatively young (median age, 28.6 years) population.⁷  Of the 13 patients who died, 40 percent were among individuals with Hgb SC or Hgb S β+ thalassemia — both traditionally considered to be mild genotypes of the disease.