Current address: University of Puerto Rico School of Medicine, San Juan, Puerto Rico
Current address: Division of Vaccines and Related Product Applications, Office of Vaccines Research and Review, Centers for Biologics Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland, United States of America
Conceived and designed the experiments: KMT CJG ARS WS EJGR EH JLMJ. Analyzed the data: KMT CJG ARS MAB. Wrote the paper: KMT. Laboratory testing: EH JLMJ. Assisted in chart reviews: KMT CJG MAB ARS. Assisted in reviewing written manuscript: CJG ARS MAB WS EJGR EH JLMJ.
The authors have declared that no competing interests exist.
The incidence and severity of dengue in Latin America has increased substantially in recent decades and data from Puerto Rico suggests an increase in severe cases. Successful clinical management of severe dengue requires early recognition and supportive care.
Fatal cases were identified among suspected dengue cases reported to two disease surveillance systems and from death certificates. To be included, fatal cases had to have specimen submitted for dengue diagnostic testing including nucleic acid amplification for dengue virus (DENV) in serum or tissue, immunohistochemical testing of tissue, and immunoassay detection of anti-DENV IgM from serum. Medical records from laboratory-positive dengue fatal case-patients were reviewed to identify possible determinants for death.
Among 10,576 reported dengue cases, 40 suspect fatal cases were identified, of which 11 were laboratory-positive, 14 were laboratory-negative, and 15 laboratory-indeterminate. The median age of laboratory-positive case-patients was 26 years (range 5 months to 78 years), including five children aged <15 years; 7 sought medical care at least once prior to hospital admission, 9 were admitted to hospital and 2 died upon arrival. The nine hospitalized case-patients stayed a mean of 15 hours (range: 3–48 hours) in the emergency department (ED) before inpatient admission. Five of the nine case-patients received intravenous methylprednisolone and four received non-isotonic saline while in shock. Eight case-patients died in the hospital; five had their terminal event on the inpatient ward and six died during a weekend. Dengue was listed on the death certificate in only 5 instances.
During a dengue epidemic in an endemic area, none of the 11 laboratory-positive case-patients who died were managed according to current WHO Guidelines. Management issues identified in this case-series included failure to recognize warning signs for severe dengue and shock, prolonged ED stays, and infrequent patient monitoring.
Dengue is a major public health problem in the tropics and subtropics; an estimated 50 million cases occur annually and 40 percent of the world's population lives in areas with dengue virus (DENV) transmission. Dengue has a wide range of clinical presentations from an undifferentiated acute febrile illness, classic dengue fever, to severe dengue (i.e., dengue hemorrhagic fever or dengue shock syndrome). About 5% of patients develop severe dengue, which is more common with second or subsequent infections. No vaccines are available to prevent dengue, and there are no specific antiviral treatments for patients with dengue. However, early recognition of shock and intensive supportive therapy can reduce risk of death from ∼10% to less than 1% among severe dengue cases. Reviewing dengue deaths is one means to identify issues in clinical management. These findings can be used to develop healthcare provider education to minimize dengue morbidity and mortality.
Dengue is a major public health problem throughout the tropics and subtropics
Primary prevention of dengue through vector control activities has had limited success worldwide
Suspected deaths due to dengue with onset of illness in 2007 were identified from three sources: 1) the passive dengue surveillance system (PDSS) maintained by the Puerto Rico Department of Health (PRDH) and Centers for Disease Control and Prevention (CDC) Dengue Branch, 2) death certificates filed at the Demographic Registry of Puerto Rico, and 3) hospital-based infection control nurse dengue surveillance system (ICNDSS) as previously described
Suspected dengue cases are reported to PDSS by health care providers who submit a serum specimen for diagnostic testing accompanied by a Dengue Case Investigation Report (DCIR). For fatal cases, autopsy tissue is occasionally sent with the serum specimen and DCIR. The DCIR includes patient demographic, clinical, travel, vaccination, and disease outcome data including whether the illness resulted in hospitalization, death or both. DCIR data are entered into an electronic data base. Deaths reported to PDSS are immediately confirmed by calling the reporting hospital.
Hospitalized suspected dengue cases are reported to the ICNDSS by nurse epidemiologists or infection control nurses. Because of a steady decline in participation, data from this reporting system are only used to augment PDSS data. When an ICNDSS case report indicated a patient death these cases were confirmed and investigated.
Death certificates with “dengue” included as a cause or contributing factor in the death were obtained on a monthly basis. The PDSS database was queried to determine if a diagnostic specimen was received for the case.
All serum specimens were tested by DENV serotype-specific, real-time, reverse transcriptase polymerase chain reaction (RT-PCR)
All serum specimens with sufficient volume remaining after dengue diagnostic testing was completed were also screened for IgM antibodies to
Autopsy tissue was sent to CDC Infectious Diseases Pathology Branch for identification of DENV antigen by immunohistochemical (IHC) microscopy and DENV-specific RT-PCR. If microscopic examination of the tissue or the clinical history was suggestive of leptospirosis (e.g., interstitial nephritis, pulmonary hemorrhage), IHC microscopy was conducted using 16 polyclonal anti-
A
A laboratory-confirmed leptospirosis case is a suspected dengue case with any of the following laboratory results: 1) isolation of
A
A
A
A
A total of 10,576 suspected dengue cases were reported with onset of symptoms in 2007; 10,171 to the PDSS only, 68 to the ICNDSS only, and 337 to both systems. There were 40 suspected dengue deaths reported to these surveillance systems and 4 additional deaths were identified only by the Demographic Registry of Puerto Rico. These latter fatal cases had no diagnostic testing performed and are not considered further in this report.
Of the 40 suspected dengue deaths, one case-patient had both tissue and paired serum specimens submitted, eight had tissue and acute serum, two had tissue and convalescent serum, four had tissue alone, one had paired serum specimens, five had only a convalescent serum specimen, and 19 had only an acute serum specimen. Eleven of the 40 suspected deaths were laboratory-positive dengue cases (
First Serum Specimen | Second Serum Specimen | Tissue | |||||||||||||
Case | DPO | DENV RT-PCR | DENV MAC-ELISA | DENV IgG ELISA | WNV RT-PCR | WNVMAC-ELISA | PRNT | Lepto IgM | DPO | DENV RT-PCR | DENVMAC-ELISA | DENV IgG ELISA | DPO | DENV RT-PCR | DENV IHC |
1 | 3 | DENV-3 | NEG | NEG | N/A | NEG | N/A | QNS | 4 | POS | POS | ||||
2 | 5 | DENV-2 | POS | NEG | N/A | NEG | N/A | QNS | |||||||
3 | 7 | NEG | POS | POS | N/A | NEG | N/A | NEG | 8 |
NEG | NEG | POS | |||
4 | 5 | DENV-3 | NEG | POS | N/A | NEG | N/A | QNS | |||||||
5 | 6 | DENV-1 | NEG | POS | NEG | POS | D1: 32D2: 128D3: 32D4: 32WNV: 8 | QNS | |||||||
6 | 5 | DENV-3 | POS | POS | N/A | NEG | N/A | QNS | |||||||
7 | 3 | NEG | POS | POS | NEG | POS | D1: 64D2: >512D3: 128D4: 16WNV: 16 | QNS | 4 | NEG | POS | POS | 4 | POS | POS |
8 | 8 | NEG | POS | POS | NEG | POS | D1: 256D2: 128D3: 64D4: 64WNV: 16 | QNS | 9 |
NEG | NEG | POS | 9 | POS | POS |
9 | 4 | POS | POS | ||||||||||||
10 | 9 | NEG | POS | POS | N/A | NEG | N/A | NEG | |||||||
11 | 4 | NEG | POS | POS | NEG | POS | D1: >512D2: 256D3: <128D4: 128WNV: <128 | QNS |
DPO = day post onset of fever; DENV = dengue virus; RT-PCR = reverse transcriptase polymerase chain reaction; MAC-ELISA = IgM antibody capture enzyme linked immunosorbent assay; ELISA = enzyme linked immunosorbent assay; WNV = West Nile virus; PRNT = plaque reduction neutralization test; IgM Lepto = IgM ELISA ImmunoDOT assay for
These samples where whole blood collected at time of death.
Of the 11 laboratory-positive case-patients who died, eight were DENV RT-PCR positive in tissue, serum or both, and three were anti-DENV IgM positive in a single serum specimen (
The median age of laboratory-positive case-patients was 26 years (range: 5 months to 78 years). Five were aged <15 years, four were 20–45 years, and two were >70 years. Seven were male. Five of six adults had at least one co-morbidity: two had asthma; one had an autoimmune hypothyroid disease; one had Type 2 diabetes mellitus (DM II) and hypertension; and one had DM II, chronic anemia, congestive heart failure, chronic obstructive pulmonary disease, and hypertension. In addition, four adults were overweight (i.e., body mass index [BMI] of 25.0–29.9), and one adult and one child were obese (i.e., BMI ≥30.0 or a BMI for age >95%).
Seven of the 11 case-patients sought medical care at least once prior to first hospital admission or presenting dead on arrival (DOA) to an emergency department (ED); three were seen by a clinician more than once but only 1 was diagnosed with a “dengue-like-syndrome”. Instead, the most common diagnoses given at these outpatient visits were upper respiratory infection with pharyngitis and/or cough, followed by acute gastroenteritis and viral syndrome. None of the seven case-patients had specimens submitted for dengue diagnostic testing until hospitalization (median 5 days post fever onset; range: 3–9 days) even though they saw clinicians early in the clinical course (median 2 days post fever onset; range 1–5 days). In addition, three case-patients had one or more warning signs for severe dengue at the time of fever defervescence, including persistent vomiting, severe abdominal pain, and narrow pulse pressure, and were sent home. A fourth case-patient, diagnosed with an upper respiratory tract infection as an outpatient, had a seizure at home the day after first being seen as an outpatient and died on the way to the hospital.
Upon final presentation to an ED, the 11 laboratory-positive case-patients had been sick a median of 4 days (range: 1–7 days). Two case-patients presented DOA and four were afebrile, three of which, had signs of shock. A seventh case-patient became afebrile while in ED and developed tachycardia, delayed capillary refill, and a narrow pulse pressure. Six case-patients had warning signs for severe dengue upon arrival to the ED including persistent vomiting (5/9) and abdominal pain (4/9). However, five of the nine case-patients were given a low (least severe) or intermediate severity triage score.
Nine case-patients were admitted to a hospital after a mean ED stay of 15 hours (median 12 hours, range: 3–48 hours) (
Inpatient Hospitalization | |||||||||||
At Initial Presentation to Emergency Department (ED) |
During Hospital Admission | ||||||||||
Case | Day post onset | First HCT % | First PLT 109/L | First WBC 109/L | Shock at ED triage | Warning signs at ED triage | LOS in ED | DHF at admit | Freq. VS at admit | No. HCT done | Medical treatment and complications |
1 | 4 | 55.2 | 234 | 12.7 | Yes | Yes | 12.5 | No | Q1 | 2 | Antibiotics, NS and ½NS given while in shock |
Prolonged shock, metabolic acidosis | |||||||||||
Acute respiratory failure and seizure | |||||||||||
2 | 1 | 35.7 | 410 | 10.4 | No | No | 5.8 | No | Q4 | 2 | Antibiotics, steroid, and ½NS given while in shock |
Prolonged shock, metabolic acidosis, DIC | |||||||||||
Blood transfusions and colloid given after seizure | |||||||||||
3 | 7 | 5.9 | 28 | 11.9 | DOA | DOA | 1.5 | N/A | N/A | N/A | Cardiopulmonary resuscitation in ED |
4 | 4 | 42.5 | 78 | 2.5 | No | Yes | 23.7 | No | Q4 | 4 | Steroid and NS given |
Prolonged shock, metabolic acidosis | |||||||||||
Changed VS to q 8 hrs; found without VS in a.m. | |||||||||||
Acute respiratory failure | |||||||||||
5 | 5 | 29.5 | 68 | 1.5 | Yes | Yes | 6.2 | Yes | Q8 | 4 | Steroid, NS and colloid given |
Blood transfusion given for bleed, hypotension | |||||||||||
Prolonged shock, metabolic acidosis | |||||||||||
Encephalopathy, suspected sepsis, antibiotics | |||||||||||
Positive urine culture, acute respiratory failure | |||||||||||
6 | 4 | 36.5 | 110 | 2.9 | No | Yes | 47.5 | No | Q6 | 11 | NS and ½ NS given while in shock |
Drop in HCT thought to be due chronic anemia | |||||||||||
Blood transfusion before discharge | |||||||||||
7 | 4 | 41.2 | 102 | 14.9 | No | Yes | 13.4 | No | Q8 | 3 | Antibiotics, NS and ½NS while in shock |
Prolonged shock, metabolic acidosis | |||||||||||
Fluid overload, acute respiratory failure | |||||||||||
Colloid given after terminal event | |||||||||||
8 | 7 | 45.4 | 8 | 8.3 | Yes | Yes | 3.0 | Yes | Q2 | 2 | Antibiotics and NS given |
Prolonged shock, metabolic acidosis | |||||||||||
Fluid overload, respiratory failure | |||||||||||
No BP taken during night; seizure in am | |||||||||||
Blood transfusions given at final code | |||||||||||
9 | 4 | — | — | — | DOA | DOA | 0.5 | N/A | N/A | N/A | Cardiopulmonary resuscitation in ED |
10 | 5 | 38.3 | 61 | 3.9 | No | No | 15.0 | No | Q8 | 3 | Steroids and NS given |
Urinary retention and muscle weakness | |||||||||||
Neuromuscular work-up not completed | |||||||||||
Acute respiratory failure; died at transfer to ICU | |||||||||||
11 | 3 | 44.3 | 49 | 4.0 | No | No | 4.3 | Yes | Q6 | 7 | Steroids and NS given |
Vaginal and gastrointestinal bleed and then, ICH | |||||||||||
Craniotomy for hematoma evacuation | |||||||||||
Cerebral artery infarction |
This table describes the clinical features of laboratory positive dengue case-patients at initial presentation to the Emergency Department (ED) and then whether patient met criteria for DHF and frequency of vital signs upon admission to the inpatient ward. The number of hematocrit levels taken during hospital stay and complications and medical treatment received are listed in last two columns.
HCT = hematocrit; PLT = platelet; WBC = white blood cell; LOS = length of stay; DHF = dengue hemorrhagic fever; VS = vital signs; NS = normal saline; IVF = intravenous fluids; BP = blood pressure; DIC = disseminated intravascular coagulation; ICU = intensive care unit; ICH = intracranial hemorrhage.
During their hospital stay, several case-patients developed warning signs for severe dengue including persistent vomiting (1/9), abdominal pain (1/9), restlessness (4/9), and mental status changes (4/9). In six cases, warning signs were not recognized as such as there were no new orders or change in the clinical management.
In the end, six of the 11 laboratory-confirmed fatal cases met criteria for DHF or DSS as determined throughout their clinical course and at autopsy (
Clinical Features of the Fatal Laboratory-positive Dengue Cases At Time of Death or End of Hospital Stay |
||||||||||||
Case | Met DHF |
Lowest PLTs×109/L | Lowest HCT % | Hemorrhagic Manifestations | Signs of Plasma Leakage | LOS triage to terminal event | ||||||
GI | Pulmonary | Vaginal | ICH | Other | Effusion | Low albumin | Hemo-concentrated | |||||
1 | No | 234 | 46.5 | No | No | No | No | Yes | Pleural | Yes | Yes | 13.0 |
2 | Yes | 53 | 9.2 | Yes | Yes | No | No | Yes | Pleural | Yes | Yes | 83.8 |
3 | No | 28 | 5.9 | UNK | No | No | UNK | Yes | UNK | UNK | No | DOA |
4 | Yes | 18 | 20.7 | Yes | No | No | No | Yes | Pleural Ascites | Yes | No | 59.2 |
5 | Yes | 50 | 29.5 | Yes | No | No | No | Yes | No | Yes | No | 71.7 |
6 | No | 34 | 24.7 | No | No | No | No | No | Ascites | Yes | No | Home |
7 | Yes | 29 | 33.6 | UNK | Yes | No | UNK | Yes | Pleural | Yes | No | 30.0 |
8 | Yes | 8 | 45.4 | Yes | No | No | UNK | Yes | Ascites | Yes | Yes | 19.7 |
9 | No | UNK | UNK | No | Yes | No | No | No | Pleural Ascites Pericardial | UNK | UNK | DOA |
10 | No | 61 | 34.5 | No | No | No | No | Yes | No | No | No | 124.8 |
11 | Yes | 32 | 26.1 | Yes | No | Yes | Yes | Yes | Pleural | Yes | No | 91.8 |
This table describes the clinical features of laboratory positive dengue case-patients at time of death or end of hospital stay.
DHF = dengue hemorrhagic fever; PLT = platelet; HCT = hematocrit; GI = gastrointestinal; ICH = intracranial hemorrhage; LOS = length of stay.
DHF criteria as defined by World Health Organization in Dengue Hemorrhagic Fever: Diagnosis, Treatment, Prevention and Control. Second edition. Geneva: World Health Organization.
Of the nine laboratory-positive case-patients admitted to a hospital, only three had capillary refill time assessed in the ED or at admission. Vital signs were measured at a median of every 3 hours in the ED but most case-patients had less frequent measurements after admission (
Eight of nine hospitalized case-patients died during hospitalization, and the other case-patient was found dead at home within 18 hours of hospital discharge (
All nine hospitalized case-patients received intravenous fluids, most commonly 0.9% normal saline (
There was frequent use of corticosteroids in laboratory-positive case-patients (
Hematocrit levels were assessed every 17 hours on average (range 10–42 hours) for the six hospitalized case-patients with clinically significant hemorrhage (
Many of the nine hospitalized case-patients developed complications including metabolic acidosis (6/9), prolonged shock (6/9), acute respiratory failure (6/9), fluid overload (3/9), and seizures (3/9) (
This case review showed that although there was a relatively low case-fatality rate among hospitalized patients with dengue during the 2007 epidemic in Puerto Rico, the clinical management of all fatal dengue cases deviated from the current WHO guidelines. Although chronic disease and bacteremia have been associated with poor outcomes, including death among adults with severe dengue
This review illustrates various levels of delay in receipt of appropriate level of care. Delay in receipt of the appropriate level of care and prolonged shock has been associated with poor outcomes among patients with severe dengue
Poor disease recognition and failure to detect increased disease severity in the ED appeared to contribute to the delay in receipt of appropriate inpatient care. Contributing factors included patients being given low triage scores and infrequent monitoring of vital signs. Lack of inpatient beds was only documented in two cases and probably did not contribute to poor outcomes. We are not aware of any published studies that indicate that use of triage scores/systems may be a factor in treatment delay for dengue as has been shown for severe sepsis
Monitoring patients closely for warning signs of severe disease and early signs of shock until at least 24 hours after fever defervescence is important as patients may rapidly deteriorate at this time. Most of our case-patients were admitted to the general inpatient ward, had infrequent monitoring of vital signs, and hematocrit levels were not ordered at a frequency necessary to monitor plasma leakage with its attendant hemoconcentration and response to fluid resuscitation. In addition, we found that warning signs and early signs of shock were not acted upon in a timely manner even when clearly documented by the nursing staff. Many hospital deaths occurred during the night or weekend, and a few had no blood pressure measurement recorded for several hours before death.
For patients with severe dengue, the mainstay of successful management is early and judicious replacement of plasma leakage with isotonic crystalloid solutions, including normal saline, Ringer's lactate, Ringer's acetate, or 5% glucose in normal saline, followed by colloid solutions in the event that shock is refractory
Most case-patients received corticosteroids even though their use has been shown to be no more effective than placebo or no treatment in reducing the number of deaths and the need for blood transfusion
Although most case-patients had clinically significant bleeding, few received packed red blood cells and none received whole blood. Infrequent monitoring of hematocrit and vital signs may have contributed to the late detection of hemorrhage. Instead, complete blood counts may have been ordered to monitor platelet counts. Platelet transfusions were ordered for most of the hospitalized case-patients but many died before receiving them. Guidelines generally recommend platelet transfusions be given to patients who have clinically significant bleeding; however, use of prophylactic platelet transfusions for dengue is a subject of debate
Lastly, our review illustrates the difficulties in making a laboratory diagnosis of dengue, especially late in the course of the disease. Even though we tested acute and convalescent specimens by all available diagnostic tests, 37.5% (15) had an indeterminate diagnosis. This occurred because the available specimen(s) were incorrectly collected with respect to the course of dengue. Seven of the 15 case-patients with an indeterminate dengue diagnosis had specimens obtained at day 4 or 5 post onset of symptoms, a period when viremia or anti-DENV IgM may be undetectable. Physicians practicing in dengue endemic areas need to be aware of including dengue in their differential diagnosis of acute febrile illness and that they must obtain serum samples for diagnostic testing early (days 1 to 3) after symptom onset. To improve diagnostic accuracy for patients who present late, samples should be collected immediately and a second collected 5 to 7 days later. Whether more sensitive diagnostic assays can be developed to increase diagnostic accuracy for specimens collected only during the critical period of dengue remains to be determined.
There are limitations to our study. This was a small case-series study which only generates descriptive data and does not identify risk factors associated with dengue deaths. The identification of risk factors must await case-control studies in a larger number of dengue fatalities. However, the high frequency of certain findings (e.g., use of non-isotonic fluids for refractory shock, infrequent monitoring vital signs, not identifying warning signs for severe dengue) suggests that they may be risk factors for poor outcomes. The other limitation is that our catchment systems may not have detected all fatal dengue cases, which may have introduced biases due to incomplete case ascertainment. However, our present surveillance approach again confirmed that in Puerto Rico, dengue continues to not be listed as the cause or underlying cause of death among laboratory-confirmed fatal cases
Clearly there is need to improve surveillance of severe and fatal cases, and to evaluate clinicians' diagnosis and clinical management of dengue in Puerto Rico. Our presumption is that, even in a dengue endemic area where the disease should be well known, sustained health care provider education and training are necessary to improve detection, diagnosis, and management of dengue and lower dengue morbidity and mortality. CDC Dengue Branch and PRDH in collaboration with a number of medical organizations used findings from this fatal case review and a physician survey that we conducted in 2007–08 (CDC data, not published) to develop a post graduate course on the clinical management of dengue for physicians in Puerto Rico which was implemented in 2009–10.
(DOC)
We would like to thank Dr. Sherif Zaki and his colleagues at the Centers for Disease Control and Prevention (CDC) Infectious Diseases Pathology Branch for their assistance in testing tissue samples for dengue virus and
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.