Diagnosis of dengue fever in a patient with early pregnancy loss

Abstract

Dengue is a mosquito-borne virus that causes an influenza-like illness ranging in severity from asymptomatic to fatal. Dengue in pregnancy has been associated with adverse outcomes including miscarriage, preterm birth and fetal and neonatal death. We present the case of a multiparous woman who presented at 9 weeks’ gestation with vaginal bleeding and abdominal cramping after a 1 month stay in Mexico. She was initially diagnosed with miscarriage with plan for outpatient follow-up. She was readmitted 3 days later with fever, retro-orbital pain, arthralgia, rash, pancytopenia and transaminitis and managed with intravenous fluids and acetaminophen. Of note, dengue serology was initially negative but retesting 2 days later was positive. It is imperative that clinicians have heightened suspicion for dengue in pregnant women with history of travel to or residence in a dengue-endemic area and consistent clinical evidence.

Background

Dengue virus is a mosquito-borne Flavivirus endemic to Asia and Latin America.¹ There has been an increase in the number of dengue cases in recent years, due in part to climate change making environments more hospitable to viral amplification and mosquito transmission, as well as spread of the virus to non-endemic regions via infected travellers.¹ Dengue fever is an influenza-like illness consisting of high fever (up to 104°F or 40°C) and systemic symptoms including severe headache, retro-orbital pain, myalgia, arthralgia and rashes. Dengue infection in pregnancy has been associated in some studies with adverse outcomes including preterm birth, miscarriage, fetal death and neonatal death, although more evidence is needed to confirm a conclusive link.^{2 3} Serological tests are considered one of the standard of care diagnostic tests to confirm dengue infection, but the antibody response mounted after infection can vary depending on the immune status and infection history of the patient.⁴ It is imperative that dengue fever be considered in pregnant women if there is clinical suspicion based on symptoms and travel history.

We report a case of dengue fever in a patient who presented with early pregnancy loss and whose presenting symptoms and travel history raised suspicion for dengue fever.

Case presentation

A 28-year-old G2P1 woman at approximately 9 weeks’ gestation by last menstrual period presented to the emergency room with vaginal bleeding and abdominal cramping 5 days after returning to the USA from a month-long trip to Oaxaca, Mexico. Her medical and surgical history was unremarkable. All haematological tests were within normal limits (haematocrit: 38.9%) and beta-human chorionic gonadotropin (β-HCG) was elevated to 5783 mIU/mL. Transvaginal ultrasound revealed pregnancy of uncertain viability with a single intrauterine gestational sac with echogenic debris, likely residual fetal pole, without cardiac activity. There was echogenic layering material within the uterine canal raising concern for blood products. The patient was counselled about suspected spontaneous abortion and discharged from the emergency room.

Three days later, the patient presented to the emergency room with fever, malaise, myalgia, arthralgia, retro-orbital pain, persistent vaginal bleeding and passage of tissue. Physical examination revealed an open cervix with blood products at the os and no significant fundal tenderness. She had normal haematological tests (haematocrit: 43.1%) and β-HCG was down trended to 3985 mIU/mL. A repeat transvaginal ultrasound was consistent with ongoing spontaneous abortion.

Investigations

On further questioning after admission to the inpatient service, the patient reported numerous mosquito bites, a viral upper respiratory infection and hand-foot-mouth disease that lasted 1 week and was treated with azithromycin in Oaxaca. She did not receive any vaccinations or prophylactic medications prior to travelling. Suspicion for septic shock or endometritis was low due to clinical signs and lack of growth on blood cultures.

On the third day of admission, the patient was noted to have waxing and waning febrile episodes associated with leukopenia, thrombocytopenia, mild transaminitis, retro-orbital pain worsening at night and a new rash. She had small pruritic papular lesions that originated on the abdomen, spread progressively to her back and all extremities, and were responsive to antihistamines. The infectious disease service was consulted for evaluation of fever of unknown origin and the possibility of dengue fever. Respiratory viral panel was negative, as were blood smears for malaria, Babesia, Ehrlichia and Anaplasma. Cytomegalovirus, HIV and Lyme antibodies were negative. Complement C3 and C4, rheumatoid factor and antinuclear antibody were normal. Serological testing for Dengue, Chikungunya and Zika viruses was negative; dengue viral non-structural protein 1 (NS-1) antigen was not sent. At this point, there were no clinical signs of ongoing endometritis and repeat transvaginal ultrasound confirmed complete abortion with no evidence of retained products. Despite negative serology, clinical suspicion for dengue fever remained high based on her symptoms and history. Repeat dengue serology on day 5 of admission was IgG negative but IgM positive. The tourniquet test, which determines capillary fragility, had been negative until also testing positive on day 5 of admission (figure 1).

Figure 1.

Tourniquet test results on day 5 of admission for the patient: (A) 1-minute post-test and (B) 10-minute post-test. The positive test result showed a maximum of 12 very small petechiae (per follicular) in a one square inch area (left part of picture B). For the tourniquet test, which measures capillary fragility, a blood pressure cuff is applied and inflated to the midpoint between the systolic and diastolic blood pressures for 5 min. The test is positive if there are more than 10–20 petechiae per square inch.

Treatment

At presentation in the emergency department, a sepsis bundle, including intravenous fluid bolus, was initiated. By the time of admission, septic abortion had been ruled out clinically and the patient was treated with intravenous gentamicin and clindamycin for suspected endometritis, given the low-grade fever and ongoing miscarriage. After 20 hours of antibiotics, the patient spiked fevers up to 102.9°F with leucopenia and elevated monocytes. Due to emerging strong clinical suspicion of dengue fever, antibiotics were discontinued on day 3 of admission and the patient was managed with standard of care intravenous fluids and acetaminophen.

The patient showed signs of haemoconcentration with a peak haematocrit level of 43.1% on admission. Daily serial haematocrit levels decreased to a nadir of 35.6% on day 4 of admission. The interval decline in haematocrit was thought to be due to haemodilution in the setting of intravenous fluids, indicated by the simultaneous decrease in other cell lines (white cell count of 1.9 x10⁹/L and platelet count of 139 x10⁹/L on day 4 of admission). In order to avoid fluid overload and given the patient’s recovering status, intravenous fluids were discontinued on day 4 of admission and serial haematocrit levels began to rise to 40.2% on day 6 (day of discharge).

Outcome and follow-up

By day 5 of admission, the patient had been afebrile for 48 hours and demonstrated resolution of symptoms, anaemia and transaminitis. The patient was clinically stable and outside the critical window for dengue-induced capillary leak at that point in time, so the patient was counselled and discharged home. The patient continued to have residual retro-orbital pain for at least 2 weeks after discharge but was otherwise well and able to return to usual activities.

Discussion

Dengue virus is transmitted primarily via the Aedes aegypti mosquito species and exists in four clinically significant serotypes, DEN-1, DEN-2, DEN-3 and DEN-4.⁴ While approximately 87% of dengue cases are asymptomatic or minimally symptomatic, a recent study estimates up to 100 million serious symptomatic infections and 25 000 deaths are caused by dengue per year.⁵ The 2009 WHO classification scheme for dengue infection includes dengue without warning signs, dengue with warning signs or severe dengue fever.⁴ Warning signs of dengue include abdominal pain or tenderness, persistent vomiting, mucosal bleeding, lethargy, liver enlargement >2 cm and an increase in haematocrit with a decrease in platelet count.⁴ Additionally, other medical or social conditions such as pregnancy, age, diabetes, renal failure or living alone can also merit categorisation as dengue with warning signs.⁴ Care should be taken to evaluate and differentiate conditions that may be occurring simultaneously and masking clinical indications of dengue, as in our case in which the patient’s abdominal pain presented in the setting of an ongoing spontaneous abortion. Our patient’s pregnancy status, along with her other symptoms, categorised her as having dengue with warning signs.

After the incubation period of the virus, which can range anywhere from 4 to 10 days, illness starts and is characterised by the following three phases: the febrile, critical and recovery phases. In the febrile stage, patients develop sudden high-grade fevers with the acute febrile phase lasting 2–7 days. The febrile phase is characterised by symptoms such as facial flushing, generalised body ache, myalgia, arthralgia and headache, some of which were seen in our patient at initial presentation.⁴ A decrease in total white cell count, also seen in our patient, is an early laboratory abnormality in this phase and should increase suspicion for dengue.⁴ The critical phase of dengue infection occurs around day 3–7 of illness, can last 24–48 hours and is marked by defervescence, increased capillary permeability and haemoconcentration (which was also seen in our patient).⁴ The third phase, which is the recovery phase, usually starts 24–84 hours after the onset of the critical phase and is characterised by reabsorption of fluid from the extravascular compartment back into the intravascular space.⁴ Excessive fluid therapy during this period can lead to pulmonary oedema or congestive heart failure.

Dengue can be confirmed through serological studies, with IgM being detectable any time after day 2 of symptoms and IgG detectable after day 15.⁵ However, an initial negative serology does not rule out dengue infection. Before day 6 of symptoms, both IgM and IgG may be negative and alternative testing, such as dengue viral antigen NS-1 or viral nucleic acid PCR, is recommended.⁴ In our case, dengue serology sent on day 3 of admission was initially negative and NS-1 antigen would have been a more beneficial test to send at that time. However, we maintained a high clinical suspicion based on the patient’s symptoms and the serology test was repeated 2 days later with positive results; viral PCR was not obtained. The 2009 WHO guidelines for dengue fever also recommend the use of the tourniquet test in its algorithm for diagnosis of dengue fever in patients who have recently lived in or travelled to a dengue-endemic area.⁴ The tourniquet test, also known as the Rumpel-Leede capillary-fragility test, is a clinical diagnostic tool for determining a patient’s haemorrhagic tendency and usually indicates thrombocytopenia. The patient in this case had daily tourniquet testing, which was negative until day 5 of admission.

Recent epidemics have shown a higher dengue incidence in adult women, leading to an increased risk for dengue in pregnancy.² It is known that infectious diseases during pregnancy should be cared for with special consideration due to the potential vulnerability of both mother and fetus. Bacterial and viral infections have been found to induce inflammatory and haemodynamic changes in the placenta leading to fetal hypoxia, as well as increasing the risk of vertical transmission directly to the fetus.⁶ In addition, high fevers alone have been found to be a risk factor for early pregnancy loss and fetal death, as well as structural and functional fetal developmental defects.⁷ Dengue can be easily confused with obstetrical medical conditions such as pre-eclampsia, HELLP syndrome (haemolysis, elevated liver enzymes and low platelets) and gestational thrombocytopenia, which makes prompt and accurate diagnosis crucial for proper treatment.⁸ Studies have associated dengue with adverse maternal outcomes including increased risk of postpartum haemorrhage, pre-eclampsia and maternal mortality, as well as with adverse perinatal outcomes including preterm labour, stillbirth and miscarriage.^{9 10}

Recent cohort studies linked dengue infection in pregnancy to a threefold increase in the risk of maternal death and a significant increase in the risk of maternal systemic complications, including acute kidney injury, shock and acute respiratory distress.^{11 12} Two case–control studies found that the risk of spontaneous abortion was four times higher and the risk of fetal death two to five times higher in dengue-infected pregnant women, depending on the severity of the infection.^{2 13} While the standard treatment for dengue fever is well established to be fluid resuscitation and acetaminophen, the timing of delivery of a pregnancy complicated by dengue remains a challenge, particularly in the third trimester.^{4 9} The data concerning this are almost exclusively case reports or series, highlighting the need for rigorous investigation of this aspect. Cases have reported deliveries ranging from expectant management to emergent caesarean section in the setting of severe dengue.⁹ The overarching key to delivery management in these cases is the balance of maternal status and disease severity with fetal status and gestational age in order to optimise the pregnancy outcome.⁹

The interplay between dengue fever and pregnancy loss is still unclear and merits further investigation. Some studies have not yet demonstrated statistically significant findings.¹³ This may be due to the fact that many of the studies analysed were case series or reports, which are limited by their small sample size and lack of control groups with which to compare outcomes and risk factors. In addition, patient characteristics such as severity of disease, gestational age or timing of infection may account for outcome discrepancies, but many of the reports of dengue cases in pregnancy failed to stratify their results by these factors. Because there are many limitations to our current knowledge of the association between pregnancy loss and dengue infection, more data and vigorous studies are required to be able to determine a conclusive link. Our patient did not report fevers prior to the commencement of her spontaneous abortion, so we cannot conclusively link her miscarriage to dengue infection or other inflammatory processes associated with dengue infection.

Despite controversy over the effects of dengue in pregnancy, the severity of potential adverse outcomes makes it imperative that clinicians take a thorough travel history and maintain a high suspicion for dengue in pregnant women with history of recent travel to or residence in a dengue-endemic area and fever for 3 days or more in the setting at least two of the following criteria: leucopenia, thrombocytopenia, rashes, pains, vomiting or a positive tourniquet test.⁴ Pregnant women should be counselled about the necessary travel precautions (insecticide, bed nets, protective clothing) if travelling to endemic regions. Currently, the dengue vaccine is reserved for persons living in endemic areas, ranging from 9 to 45 years of age, who have had at least one documented Dengue virus infection previously.⁴ Promoting knowledge of risk factors and common features of dengue fever in pregnant women would improve risk assessment, patient counselling and management.

Learning points.

• Dengue fever is a viral tropical disease endemic to Asia and Latin America with increasing prevalence in recent years. It is diagnosed based on history and clinical symptoms, haematological studies and serological or virological tests.

• Clinicians should have a high suspicion for dengue fever in pregnant women with history of recent travel to or residence in a dengue-endemic area, retro-orbital pain, fever, leucopenia, thrombocytopenia and/or a positive tourniquet test.

• Dengue viral antigen non-structural protein 1 or viral nucleic acid PCR is recommended in the first 5 days of symptoms as serology testing for both IgM and IgG may be negative before day 6 of symptoms.

• Even if initial tests for dengue have negative results, pregnant patients should be carefully monitored and testing should be repeated if high clinical suspicion persists due to potential associated adverse pregnancy outcomes.

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