Pulmonary hemorrhage syndrome associated with an autochthonous case of dengue hemorrhagic fever.

Abstract: Dengue fever is a major public health problem worldwide. Dengue hemorrhagic fever, a much rarer form of the disease, occurs when a person previously infected with dengue is re-infected with a different viral serotype. In recent years the infection rates of dengue and both clinical syndromes have increased along the United States-Mexico border. We present the case of a 61-year-old Laotian female who presented with a 1-week history of fever, altered mental status, oral ulceration, and rash. The patient developed diffuse pulmonary hemorrhage and anemia requiring multiple transfusions. She eventually sustained multi-organ system failure and expired. Both the titer data and serologies were consistent with the diagnosis of dengue hemorrhagic fever. We hypothesize that this syndrome was the result of re-infection occurring within the United States. This case is also unusual in that it is the second reported in the literature of pulmonary hemorrhages associated with dengue hemorrhagic fever.

Key Words: dengue hemorrhagic fever, hemoptysis, pulmonary hemorrhage

**********

The term "dengue" was introduced into the English medical literature in 1827. It is derived from the Swahili word "Ki-denga pepo," which describes a sudden cramp-like seizure caused by an evil spirit. (1,2) Reports of illness with symptoms similar to that of dengue fever date back to the Chin and Tang dynasties of China. (3) The disease was thought to be a water poison somehow spread by flying insects. Later reports of similar outbreaks in Philadelphia in 1780 (1) and in Panama in 1699 (4) may have also been dengue. Up until 1940, dengue had been characterized by large but infrequent outbreaks isolated in a few geographic areas. Increased transmission of the virus has since led to an increase in the distribution of epidemics to nonindigenous areas, and an increase in the frequency of epidemics.

Although dengue remains primarily a tropical disease, the spread of different serotypes to nonindigenous areas has been attributed to the redistribution of the virus' principle vector, the Aedes aegypti mosquito. Subsequent increases in the number of reported dengue fever cases have become an important global health concern in recent years. (5,6)

Dengue is characterized by four different serotypes (DEN-1, DEN-2, DEN-3, and DEN-4). Infection with any one of these serotypes leads to classic dengue and lifelong immunity to that particular serotype. However, dengue hemorrhagic fever (DHF), a more serious form of dengue, occurs when a person is infected with a second, different serotype. Typical manifestations of DHF include an initial sudden onset of fever, usually lasting for 2 to 7 days. After defervescence, patients usually have thrombocytopenia, signs of hemoconcentration, petechiae, purpuric lesions, and ecchymosis. Less frequent symptoms include epistaxis, bleeding gums, gastrointestinal hemorrhages, and hematuria. Pulmonary manifestations are rarely seen in DHF. In the past, pleural effusions and pneumonitis have been described as a rare complication of DHF. (7) Hemoptysis and pulmonary hemorrhages have been described only once in the literature. (8) In this report, we describe a patient with DHF who subsequently developed pulmonary hemorrhages and subsequent acute respiratory distress syndrome (ARDS).

Case Report

The patient was a 61-year-old Laotian female who lived in Val Verde, Texas. She presented with a one week history of high fever, altered mental status, painful mouth ulcers, and rash. She initially sought medical attention by visiting a dentist in Acuna, Mexico. She was given a mouthwash for pain relief and ampicillin. Her family noted mental status changes 2 or 3 days before presentation to the hospital. The family denied any recent travel history, other than to Mexico. There were no ill contacts at home. Her husband noted that they lived on a farm near a pond in an area heavily infested with mosquitos. They had outside cats, chickens and pigeons. Her past medical history was significant for hypertriglyceridemia, gastro-esophageal reflux disease (GERD), monoclonal gammopathy of undetermined significance (MGUS), and a history of a positive purified protein derivative (PPD) test. Her surgical history was significant for a hysterectomy with a bilateral salpingo-oophorectomy, abdominal aortic aneurysm repair, and a C-section. Her medications were gemfibrozil, amoxicillin, omeprazole, calcium supplements, and estrogen. She had a remote smoking history and did not drink alcohol. On presentation, her temperature was 101[degrees]F, respiratory rate 24 per minute, heart rate 115 bpm, and blood pressure was 136/73 mm Hg. She was alert, but not oriented, but was able to follow simple commands. On examination, blood was noted in her oropharynx with ulcerated lesions on the oral mucosa, but no active sources of hemorrhage were identified. A diffuse, nonblanching, confluent rash was present on her back, buttocks, palms and soles. She had mild right upper quadrant tenderness without hepatosplenomegaly. The rest of her examination, including pulmonary, was unremarkable. Pertinent laboratory results are listed in Table 1.

Initially she received cefotaxime and levofloxacin in the emergency room. She was admitted to the intensive care unit and was initially treated supportively with intravenous fluids. She was started on doxycycline, aztreonam, and ceftriaxone empirically to cover for Gram-negative and Gram-positive bacteremia, meningococcemia, and Rocky Mountain Spotted Fever. (Bacterial agents such as meningococcus and rickettsial species were considered due to her presentation with fever and diffuse rash.) Aztreonam was chosen in lieu of an aminoglycoside due to her compromised renal function (see Table 1 for initial laboratory values) and to provide additive Gram-negative coverage with ceftriaxone. A computed tomography (CT) scan of the head and cerebrospinal fluid analysis was unremarkable. Skin biopsy of the rash demonstrated papillary dermal edema with perivascular lymphocytic inflammation, red blood cell (RBC) extravasation, and necrotic keratinocytes. There was mild deposition of C3 and fibrin seen in the dermal vessels. Serologies for rickettsial and fungal infections, viral hepatitis, human immunodeficiency virus, syphilis, and connective tissue diseases were unremarkable for acute infection. Bacterial and fungal cultures of blood were negative. Fungal antibody studies were negative. Several days after admission she developed respiratory distress requiring intubation and mechanical ventilation. After intubation, she became increasingly hemodynamically unstable. She developed diffuse pulmonary hemorrhages, hemepositive stools, severe respiratory acidosis, and hypercapnia. Her pancytopenia was evaluated by bone marrow biopsy, which demonstrated marked diffuse hypocellularity with focal aplasia. No evidence of primary hematopoietic or metastatic malignancy or fibrosis was present.

Her chest CT showed diffuse infiltrates and bilateral effusions (Fig. 1). On hospital day 5 a bronchoscopy was performed in which biopsies showed hemosiderin-laden macrophages and blood-tinged sputum. Dengue serologies (both IgM and IgG) were elevated whereas other viral titers were unremarkable. Blood cultures for bacteria and fungi were negative. Her hospital course was also notable for severe anemia requiring multiple transfusions and the development of ARDS.

During the remainder of the hospital course, she experienced multiple episodes of agitation and hypertension with intervening episodes of hypotension and desaturation requiring constant titration of sedation, fluid resuscitation, and vasopressors. Despite aggressive treatment, she continued to have frequent fevers up to 103[degrees]F. She eventually developed multi-organ system failure and expired on hospital day 17. At autopsy, the cut surfaces of each of the pulmonary lobes were dark red with marked edema and congestion. The right and left lungs weighed 1,240 g and 920 g, respectively (normal 420-680 g). Histologic sections showed diffuse alveolar damage changes (Fig. 2a & b). Before her death, dengue serologies were taken for serotype analysis via plaque reduction titers (using the protocol as described by Morens et al (9)). These results are shown in Table 2. Antibodies for the four dengue serotypes were assessed by plaque reduction neutralization and showed elevated titers for DEN-1, DEN-2, and DEN-3.

Discussion

This patient had a clinical spectrum consistent with DHF. Detailed serologic analysis was most consistent with this diagnosis and suggested infections with serotypes DEN-1, DEN-2 and possibly DEN-3. We hypothesize that her initial infection occurred in her home country of Laos, and re-infection occurred in the United States. Pulmonary manifestations of DHF such as pleural effusions, although rare, have been reported. (7) Hemoptysis has been reported in 1.4% of dengue infections. (10) On review of the literature, we have found only one other report describing pulmonary hemorrhages and hemoptysis in DHF. (8) This case is unique in that the extent of the pulmonary involvement was demonstrated by histologic sections. The pathogenesis of bleeding in DHF patients is not well understood. It is thought to be a multi-factorial process with abnormalities in the coagulation cascade, thrombocytopenia, platelet dysfunction, disseminated intravascular coagulation, and vascular defects. Vascular permeability has been thought to be mediated by histamine release. (11) It is interesting to note that in our case, throughout the patient's hospital course there were no significant changes in serum coagulation factor effects; she never developed severe thrombocytopenia (platelet counts remained [greater than or equal to]40 X [10.sup.3]). These findings may suggest that vascular permeability, platelet dysfunction, or other factors may also play an important role in DHF-related hemorrhage.

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

Conclusion

Hemoptysis and pulmonary hemorrhages are rare complications of DHF. Only one other case of DHF with such a presentation exists in the literature. Pathologic sections of the lung tissue showed diffuse hemorrhage completely filling the alveolar spaces as well as a diffuse alveolar damage-like reaction pattern along the surface of the alveolar septa. The patient failed to develop either a significant coagulopathy or thrombocytopenia, both of which are often seen in DHF and are thought to result in spontaneous hemorrhage. These findings may suggest that vascular permeability, platelet dysfunction, or other factors may play an important role in DHF-related hemorrhage.

Table 1. Pertinent laboratory values (normal values in second column)

Blood chemistries
  BUN 109 H                       5-20 mg/dL
  Creatinine 2.9 H                0.7-1.3 mg/dL
  Alkaline phos 39                35-106 IU/L
  AST 123 H                       4-50 IU/L
  ALT 22                          3-55 IU/L
  Total Bili 0.6                  0.2-1.2 mg/dL
  LDH 507 H                       11-213 IU/L
  Lipase 347 H                    10-204 IU/L
  Lactate 0.9                     0.7-2.1 mmol/L
  Myoglobin 772 H                 10-60 ng/dL
  Serum/urine tox screen
    negative
  TSH 0.06 L                      0.4-4.1 IU/mL
  Free T4 1.3                     0.7-1.8 ng/dL
CBC
  WBC 1.9 L                       3.4-9.8 X
                                  [10.sup.3]
                                  with normal
                                  differential
  Hemoglobin 8.7 L                11-16 g/dL
  Hematocrit 25.7 L               34-47%
  Platelets 44.2 L                142-362 X
                                  [10.sup.3]
  MCV 91.2                        80-99 fL
Urine labs
  Protein 300 H                   normal-negative
  WBC 1-4 H                       0-4/HPF
  RBC 30-40 H                     <4/HPF
  Nitrites negative
  Leukocyte esterase trace
  Bacteria trace
DIC panel
  Degraded fibrin products
    <5                            negative mcg/mL
  Fibrinogen 406 H                167-378 mg/dL
  D-dimer 1.0                     <2.0 mcg/mL
  PT 12.0                         10-13 sec
  APTT 32                         22-32 sec
  INR 1.03                        0.9-1.14
  Cryoglobin none detected
  C3 44 L                         90-180 mg/dL
  C4 5 L                          20-65 mg/dL
Serologies for inflammatory disorders
  ESR 75 H                        0-30 mm/h
  C-reactive protein 12.7 H       0-0.5 mg/dL
  P-ANCA 100                      0.0-150 AAU/mL
  C-ANCA 45                       0.0-150 AAU/mL
  RF negative
  ANA negative
  Anti SSa (Ro) negative
  Anti SSb (La) negative
  Anti RNP negative
  Anti Smith Ab negative
  Anti glomerular Ab negative
Virus and bacteria serologies
  HIV negative
  Hepatitis B surface Ag
    negative
  Anti-HepB core positive
  Anti-HepC negative
  Anti-HepB surface AB
    positive
  Parvovirus B19 IgG 6.3 H        0-0.9
  Parvovirus B19 IgM 0.2          0-0.9
  Q fever negative
  RMSF negative
  R typhus negative
  Ehrlichia chaffee negative
  Strep DNase B Ab 1:240          [less than or equal to]1:85 titer
  ASO 12                          [less than or equal to]100 Todd Units
  RPR negative
  Dengue IgG 12.28 H              0-0.89
  Dengue IgM 0.94 H               0-0.89

Table 2. Dengue serologies

Dengue virus antibody titers
  IgM                                           1:100
  IgG                                          >1:12,800
Plaque reduction neutralization (9) to DEN
    1,2,3, and 4 (80% reduction titers)
  DEN 1                                         1:80
  DEN 2                                         1:320
  DEN 3                                         1:40
  DEN 4                                         1:10

Acknowledgment

The authors would like to thank the Graphic Arts Department at Brooke Army Medical Center for their assistance in preparing the article's figures for publication.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9707-0688

References

1. Halstead SB. Dengue hemorrhagic fever-a public health problem and a field for research. Bull of the WHO 1980;58(1):1-21.

2. Gubler DJ. Dengue and dengue hemorrhagic fever. Clin Microbiol Rev 1998;11:480-496.

3. Gubler DJ and Kuno G (eds): Dengue and Dengue Hemorrhagic Fever. London, CAB International, 1997, pp 1-22.

4. McSherry JA. Some medical aspects of the Darien Scheme: was it dengue? Scottish Med J 1982;27:183-184.

5. Kuno G. Review of the factors modulating dengue transmission. Epidemiologic Rev 1995;17(2):321-335.

6. Dengue Hemorrhagic Fever: Diagnosis, Treatment, Prevention and Control. Geneva, Switzerland, World Health Organization, 1997, ed 2, pp 1-11.

7. Nelson ER. Haemorrhagic fever in children in Thailand. J Paediatrics 1960;56:101-108.

8. Liam CK, Yap BH, and Lam SK. Dengue fever complicated by pulmonary haemorrhage manifesting as haemoptysis. J Trop Med & Hygiene 1993;96:197-200.

9. Morens, M., Halstead SB, Repik PM, et al. Simplified plaque reduction neutralization assay for dengue viruses by semimicro methods in BHK-21 cells: comparison of the BHK suspension test with standard plaque reduction neutralization. J Clin Microbiol 1985;22(2):250-254.

10. Hayes GC, Manaloto CR, Gonzales A, et al. Dengue infections in the Philippines: clinical and virological findings in 517 hospitalized patients. Am J of Trop Med & Hygiene 1988;39:110-116.

11. Rodriguez-Tan RS, and Weir MR. Dengue: a review. Texas Med 1998;94(10):53-59.

RELATED ARTICLE: Key Points

* Pulmonary hemorrhages and hemoptysis are rare presentations in dengue hemorrhagic fever; only one other case has been reported in the literature with a presentation of pulmonary hemorrhages and hemoptysis.

* The patient never developed a severe thrombocytopenia or a laboratory-confirmed coagulopathy, possibly suggesting that changes in vascular permeability, platelet dysfunction, or other factors may be responsible for bleeding seen in dengue hemorrhagic fever.

MAJ Robert F. Setlik, MD, PHD, MC, USA, COL Daniel Ouellette, MD, MC, USA, COL Julia Morgan, DO, MC, USA, COL C. Kenneth McAllister, MD, MC, USA, LTC David Dorsey, MD, MC, USA, MAJ Brian K. Agan, MD, MC, USAF, MAJ Lynn Horvath, MD, MC, USA, CPT Michelle K. Zimmerman, MD, MC, USAF, and MAJ Bret Purcell, MD, PHD, MC, USA,

From the Departments of Internal Medicine, Pulmonary and Critical Care Medicine, and Infectious Diseases, Brooke Army Medical Center, Fort Sam Houston, TX, the departments of Infectious Diseases and Pathology, Wilford Hall Medical Center, Lackland AFB, TX, and the United States Army Research Medical Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD.

The views expressed in this article are those of the authors and do not reflect the official policy or position of the US Army, the US Air Force, the US Department of Defense, or the US Government.

Reprint requests to MAJ Robert F. Setlik, MD, PhD, Internal Medicine Department, Brooke Army Medical Center, 3851 Roger Brooke Drive, Fort Sam Houston, TX, 78234. Email: [e-mail]