In The Literature

Do Not Get Zika Virus Infection Before You Get Dengue

Katzelnick LC, Narvaez C, Arguello S, et al. Zika virus infection enhances future risk of severe dengue disease. Science 2020. doi: 10.1126/science.abb6143.

The Zika virus pandemic of 2013–2017 affected many regions that were endemic for another mosquito-borne flavivirus, dengue. Because of the known antigenic cross-reactivity among flaviviruses, this raised concern about the potential for unfavorable outcomes in patients with previous dengue virus infection who were subsequently infected with the Zika virus. This concern was well founded because of the known effect of serial infection with different serotypes of dengue virus, of which there are 4. Such sequential infection may result in disease of increased severity, including the development of dengue hemorrhagic fever, and is the result of antibody-dependent enhancement. Antibody-dependent enhancement results from the presence of a cross-reactive but non-neutralizing antibody that facilitates viral entry and infection of host cells, resulting in increased infectivity and virulence, probably through interaction with the Fc receptor [1]. Fortunately, there proved to be no evidence that prior dengue infection enhanced the severity of Zika.

But since neither virus was going to disappear from the planet, the question of whether prior Zika infection would lead to increased severity of a subsequent dengue episode inevitably arose. This issue became of increasing relevance when there was a major resurgence of dengue in Latin America in 2019. Fortunately, an ongoing study of a large (N = 3800) cohort of children in Managua, Nicaragua, had been established in 2004 to study dengue. The study was adjusted to also evaluate chikungunya and Zika virus infections when these pathogens were introduced into the country in 2014 and 2016, respectively.

Beginning in 2004, all children in the cohort underwent yearly testing for antibody to dengue virus. All children with suspected dengue, an undifferentiated febrile illness, or (starting in 2016) those with rash in the absence of fever underwent reverse transcriptase–polymerase chain reaction testing for all 3 viruses. Since then, yearly testing for antibody to Zika virus was performed in the cohort. During the 2019 resurgence, 375 children in the cohort had symptomatic dengue, with all virologically confirmed cases of dengue caused by serotype 2.

Overall, 8.8% of the cohort experienced a symptomatic dengue virus infection in 2019–2020, but the rate in those with a single prior Zika virus infection was 12.1% while it was only 3.5% without a prior identified flavivirus infection. The risk of dengue shock syndrome or dengue hemorrhagic fever was 0% in prior flavivirus-naive children, while it was 1.1% (95% confidence interval [CI], .3–1.8%) in those with 1 prior Zika virus infection and .9% (95% CI, 0–3.3%)—differences that are small but perhaps of concern. These observations are consistent with a conclusion that experiencing a Zika virus infection increases the risk that a subsequent dengue virus infection will be severe.

The probability of symptomatic dengue virus infection was only 2.5% in children with 2 prior dengue virus infections, while it was 9.5% in those with a single dengue infection followed by a Zika infection. The occurrence of Zika infection after 2 prior dengue infections did not affect the low incidence of symptomatic dengue. The probability of experiencing worrisome or severe dengue was 5.4% for subjects with 1 prior dengue virus infection, 5.9% with 1 prior episode of Zika, and 5.9% with 1 dengue and 1 Zika virus infection.

Children with any level of pre-existing cross-reacting antibody to dengue virus were at significantly greater risk of symptomatic dengue than were children who were flavivirus naive, with those with an intermediate level being at the greatest risk, including the risk of severe dengue.

The investigators conclude that either a prior single Zika virus infection or a single prior dengue virus infection can enhance subsequent dengue serotype 2 disease. In contrast, the risk of symptomatic dengue was low after having had 2 previous dengue episodes and this was unaffected by intervening Zika virus infection. These observations have important implications for vaccine design and sequencing.

Reference

Persistence of Tropical Splenomegaly in Refugees Living in the United States

Zambrano LD, Jentes E, Phares C, et al. Clinical sequelae associated with unresolved tropical splenomegaly in a cohort of recently resettled congolese refugees in the United States—multiple states, 2015–2018. Am J Trop Med Hyg 2020;103(1):485–93. doi: 10.4269/ajtmh.19–0534. Epub 2020 Apr 30. PubMed PMID: 32372751. PubMed Central PMCID: PMC7356405.

Splenomegaly in residents of tropical regions of the world—tropical splenomegaly (TS)—may be due to any of a large number of causes but is often related to infections endemic in the patients’ countries of origin. The most frequently reported etiology is chronic malaria; hence, the alternative term, hyperreactive malaria syndrome, but this is often an etiologic diagnosis of exclusion that is frequently applied when testing fails to determine a cause.

Because of an apparent increase in prevalence of TS, enhanced screening of 987 US-bound Congolese refugees in March and July of 2015 was performed and 145 (15%) were found to have splenomegaly, 122 (45%) of whom had massive splenomegaly, as defined by World Health Organization ultrasound examination criteria. Enhanced testing was performed for malaria, schistosomiasis, leishmaniasis, hepatitis, tuberculosis, and sickle cell anemia. Only 29.6% had evidence of malaria by rapid diagnostic tests (RDTs) and/or smears, but all patients with splenomegaly were presumptively treated twice with artemether and lumefantrine; all also received praziquantel.

A further recommendation was made by the Centers for Disease Control and Prevention to administer primaquine to all with splenomegaly after screening for G6PD deficiency. A total of 143 of the subjects resettled in 23 states.

Based on the available published information, it was assumed that malaria treatment would result in rapid resolution of splenomegaly in these patients, but anecdotal reporting suggested that this was not always the case. These observations led to an investigation designed to understand the later outcomes of subjects with TS. The importance of an improved understanding of TS was amplified by the knowledge that approximately 28 000 refugees from the Democratic Republic of Congo had resettled in the United States in 2015 and 2016.

Medical records were obtained for 130 case patients (92 from the initial cohort) from 9 states and 102 matched case controls. Almost three-fourths of cases were younger than 25 years of age and 59.2% were male. Of the 130 cases, 95 had detectable splenomegaly on initial evaluation in the United States (the splenomegaly had resolved in the remainder in the interval since their examination abroad). Medical records beyond 6 months after US arrival were available for 85 individuals and 58 had a splenic examination recorded, 45 (77.6%) of whom had physical or ultrasound evidence of splenomegaly. These 45 represented 52.9% of all those with records available later than 6 months after arrival in the United States.

Fourteen (60.9%) of 23 with available medical records covering more than 18 months after arrival in the United States still had splenomegaly. Among all patients whose splenomegaly was still present at 6 months or later, it persisted for a median duration of 9.4 months (interquartile range, 2.7–15.9 months), with an observed (but not true) maximum of 27.9 months. The mean duration of splenomegaly did not differ by Plasmodium species, nor did it differ by receipt of primaquine, which was prescribed for 37.2% of case patients. There was evidence of familial clustering of splenomegaly based on identification of cases in families not previously identified, with many requiring ultrasound examination for detection.

Of 112 cases for whom some form of testing for malaria was at some point performed, 65 (58.0%) were test-positive by smear, RDT, and/or polymerase chain reaction. Only 10 controls were tested and 3 were positive by at least 1 test for malaria. Of 17 case patients with persistent splenomegaly who were tested, 11 (64.7%) had detectable antibody to schistosomes and 6 had persistent eosinophilia. Anemia, thrombocytopenia, and elevated serum alkaline phosphatase were each more common in subjects with persistent splenomegaly.

This study demonstrates that TS does not disappear upon leaving an endemic area and that, even though many have evidence of Plasmodia infection, antimalarial treatment does not necessarily prevent its persistence. The investigators also conclude that primaquine should be administered to patients with TS and that retreatment with praziquantel should be administered to those with persistent splenomegaly and eosinophilia. It can also be concluded that ultrasound screening of family members for the presence of splenomegaly should be considered. Finally, we need much more research to fully understand TS.