Chief of ServiceU.Rampal .MD 1/3/12

HOPI

Patient is a 53 year old Indian female who came back 4 days ago from St Lucia after a 8 day vacation and presented to the ER with chief complains of fever with chills since 1 day ,associated with 2-3 episodes of diarrhea on the day of admission.

Fever was high grade, episodic associated with chills and rigors.

Diarrhea was watery large volume 3 episodes since day of admission ,no blood or mucous noticed in stool associated with nausea, no vomiting.

Pertinent negativesNo headaches/retro-orbital pain

No recent sick contacts

No insect bites

No myalgia or arthralgia or rash

No throat pain or cough or chest pain or shortness of breath

No dysuria or increased frequency of micturition

No abdominal pain or flank pain.

No vaginal discharge or vaginal bleeding or vaginal pruritus.

Past surgical/medical History

Hysterectomy

Disc prolapse-takes Percocet for back pain.

Social history

Denies alcohol/smoking/drug use

Lives with her children and is on disability secondary to chronic back pain.

Family history –

Mother –diabetes

Father -healthy

Physical exam

Vitals-

BP-94/51, Pulse 104, RR-18, Temp-100.3

o General appearance

Calm and comfortable ,in no acute distress, age appropriate Indian female who was alert, awake and oriented to time place and person

Head –AT/NC

Pupils-PERRLA

No pallor/icterus

No tonsillar enlargement, pharyngeal erythema

No cervical lymphadenopathy

No thyromegaly, EOM –wnl

No neck rigidity.

CVS- PMI non displaced,

S1 ,S2 + no murmurs ,rubs or gallops.

o RS- good air entry b/l

Normal vesicular breath sounds heard b/l

No rhonchi/crackles

o Abdomen-non distended

o Non tender , no hepatosplenomegaly, BS +

o No CVA tenderness

Extremities-

No pedal edema, no rash, no joint swelling or tenderness

Skin-no petechiae/rash

o Neurological

AA0*3,

Cranial nerve intact

Deep tendon reflexes 2+ b/l

Babinski sign negative

Labs

BMP

Na + -134,K+3.5,

BUN-10,creatinine-0.83,

Chloride-99,bicarbonate-26

• CBC

wbc- 4.8, HB-9.7,HCt-30.2,platelets-200 mcv- 60.2

RDW-15.2

UA

UA

Trace protein

Bacteria moderate

Leukocyte esterase large

WBC- 10-20

Epithelial cells -few

Liver panel

Total protein 7.3,albumin 3.6

T .bili -0.7, D.bili-0.1

AST-31,ALT-13, ALP-71

Chest x-ray

No infiltrate/no cardiomegaly

EKG- normal sinus rhythm

investigations

Iron studies

Stool studies

For ova parasites, leukocytes, occult blood , c. difficile

Malaria prep

US abdomen

Differential

Traveller’s diarrhea

o UTI

Malaria

• Dengue fever

o Typhoid or paratyphoid fever

Hepatitis A

management

Ciprofloxacin 400 mg IV q12

Fluid resuscitation

Results of investigations orders

• Malaria prep negative

• Urine c/s no growth

• Stool ova parasites- negative ,c. diff negative ,no stool leukocytes, occult blood negative.

• Iron -22 ,tibc241,ferritin 120

ad-mis-sion

day1 day2 day3 day4 ay50

20

40

60

80

100

120

140

160

180

200

Platelet trendK

/UL

Further investigations

Dengue fever antibodies IgG and IgM

Hemoglobinopathy evaluation

investigtions

Day WBC Platelets Temp(max)

admission 4.8 200 100.3

1 3.0 166 100.1

2 2.9 165 102.7

3 3.3 132 101.3

4, 6 AM 3.2 48 100.3

4 ,1 PM 3.3 44 97.9

5 4.6 33 97.9

6 5.2 43 97.5

7 5.8 60 98

8 7.5 97 98

Dengue fever antibodies

IgG-6.73

IgM-4.82

Hemoglobinopathy evaluation

Presumptive heterozygous for beta-thalassemia

With increased Hb A2-4.8%

Mildly decreased Hb a-95%

Follow up

Patient was initially scheduled for follow up at medical clinic and with hem/onc for further evaluation of thalassemia trait, however patient being a resident of Brooklyn wanted to follow up with her PMD.

Patient was explained to return to ER if any warning signs of blood loss.

DENGUE

Epidemiology

Some 1.8 billion (more than 70%) of the population at risk for dengue worldwide live in member states of the WHO South-East Asia Region and Western Pacific Region, which bear nearly 75% of the current global disease burden due to dengue

Dengue in the Americas Interruption of dengue transmission in much the WHO Region of the Americas resulted from the Ae. aegypti eradication campaign in the Americas, mainly during the 1960s and early 1970s. However, vector surveillance and control measures were not sustained and there were subsequent re-infestations of the mosquito, followed by outbreaks in the Caribbean, and in Central and South America (1).

The Southern Cone countries

Argentina, Brazil, Chile, Paraguay and Uruguay are located in this sub region.

This sub region includes Bolivia, Colombia, Ecuador, Peru and Venezuela, and contributed 19% (819 466) of dengue cases in the Americas

1. PAHO. Plan continental de ampliacion e intensificacion del combate al Aedes aegypti. Informe de un grupo de trabajo, Caracas, Venezuela. Abril 1997. Washington, DC, Pan American Health Organization, 1997

Dengue in the Americas

Central American countries and Mexico

During 2001–2007, a total of 545 049 cases, representing 12.5% of dengue in the Americas

Caribbean countries

In this sub region 3.9% (168 819) of the cases of dengue were notified, with 2217 DHF cases and 284 deaths

North American countries

The majority of the notified cases of dengue in Canada and the United States are persons who had travelled to endemic areas in Asia, the Caribbean, or Central or South America (2). From 2001 to 2007, 796 cases of dengue were reported in the United States, the majority imported. Nevertheless, outbreaks of dengue in Hawaii have been reported, and there were outbreaks sporadically with local transmission in Texas at the border with Mexico

(2)Centers for Disease Control and Prevention. Travel-associated dengue -- United States, 2005. Morbidity and Mortality Weekly Report, 2006, 55(25):700--702.

DENGUE IN INTERNATIONAL TRAVEL

Travellers play an essential role in the global epidemiology of dengue infections, as viaremic travellers carry various dengue serotypes and strains into areas with mosquitoes that can transmit infection

From the data collected longitudinally over a decade by the GeoSentinel Surveillance Network (www.geosentinel.org) it was possible, for example, to examine month-by- month morbidity from a sample of 522 cases of dengue as a proportion of all diagnoses in 24 920 ill returned travellers seen at 33 surveillance sites. (3)

(3)Schwartz E. Seasonality, annual trends, and characteristics of dengue among ill returned travelers, 1997–2006. Emerging Infectious Diseases, 2008, 14(7).

Information about dengue in travellers, using sentinel surveillance, can be shared rapidly to alert the international community to the onset of epidemics in endemic areas

The information can also assist clinicians in temperate regions -- most of whom are not trained in clinical tropical diseases -- to be alert for cases of dengue fever in ill returned travellers.

The clinical manifestations and complications of dengue can also be studied in travellers (most of them adult and non-immune) as dengue may present differently compared with the endemic population (most of them in the pediatric age group and with pre-existing immunity)

Transmission

The virus

1. Dengue virus (DEN) is a small single-stranded RNA virus comprising four distinct serotypes (DEN-1 to -4). These closely related serotypes of the dengue virus belong to the genus Flavivirus, family Flaviviridae.

2. The mature particle of the dengue virus is spherical with a diameter of 50nm containing multiple copies of the three structural proteins,

• Capsid ,C

• Precursor of membrane protein ,prM

• Envelope protein,E

The vector

The various serotypes of the dengue virus are transmitted to humans through the bites of infected Aedes mosquitoes, principally Ae. aegypti.

This mosquito is a tropical and subtropical species widely distributed around the world, mostly between latitudes 35 0N and 35 0S.

The immature stages are found in water-filled habitats, mostly in artificial containers closely associated with human dwellings and often indoors

• Studies suggest that most female Ae. aegypti may spend their lifetime in or around the houses where they emerge as adults. This means that people, rather than mosquitoes, rapidly move the virus within and between communities.

The Host

After an incubation period of 4--10 days, infection by any of the four virus serotypes can produce a wide spectrum of illness, although most infections are asymptomatic or subclinical

Primary infection is thought to induce lifelong protective immunity to the infecting serotype .

Individual risk factors determine the severity of disease and include secondary infection, age, ethnicity and possibly chronic diseases (bronchial asthma, sickle cell anaemia and diabetes mellitus)

Seroepidemiological studies in Cuba and Thailand consistently support the role of secondary heterotypic infection as a risk factor for severe dengue, although there are a few reports of severe cases associated with primary infection (4,5,6,7).

The time interval between infections and the particular viral sequence of infections may also be of importance.

Antibody-dependent enhancement (ADE) of infection has been hypothesized (8,9) as a mechanism to explain severe dengue in the course of a secondary infection and in infants with primary infections.

Host genetic determinants might influence the clinical outcome of infection (10,11), though most studies have been unable to adequately address this issue. Studies in the American region show the rates of severe dengue to be lower in individuals of African ancestry than those in other ethnic groups. (11) 10. Kouri GP, Guzman MG. Dengue haemorrhagic fever/dengue shock syndrome: lessons

from the Cuban epidemic, 1981. Bulletin of the World Health Organization, 1989, 67(4):375--380. 11. Sierra B, Kouri G, Guzman MG. Race: a risk factor for dengue hemorrhagic fever. Archives of Virology, 2007, 152(3):533--542.

The dengue virus enters via the skin while an infected mosquito is taking a bloodmeal.

During the acute phase of illness the virus is present in the blood and its clearance from this compartment generally coincides with defervescence.

Humoral and cellular immune responses are considered to contribute to virus clearance via the generation of neutralizing antibodies and the activation of CD4+ and CD8+ T lymphocytes.

Plasma leakage, haemoconcentration and abnormalities in homeostasis characterizesevere dengue.

Plasma leakage, haemoconcentration and abnormalities in homeostasis characterizesevere dengue.

Recent data suggest that endothelial cell activation could mediate plasma leakage (12,13).

Plasma leakage is thought to be associated with functional rather than destructive effects on endothelial cells.

Activation of infected monocytes and T cells, the complement system and the production of mediators, monokines, cytokines and soluble receptors may also be involved in endothelial cell dysfunction. 13. Cardier JE et al. Proinflammatory factors present in sera from patients with acute

dengue infection induce activation and apoptosis of human microvascular endothelial cells: possible role of TNF-alpha in endothelial cell damage in dengue. Cytokine, 2005, 30(6):359--365.

Thrombocytopenia may be associated with alterations in megakaryocytopoieses by the infection of human hematopoietic cells and impaired progenitor cell growth, resulting in platelet dysfunction (platelet activation and aggregation), increased destruction or consumption (peripheral sequestration and consumption).

Hemorrhage may be a consequence of the thrombocytopenia and associated platelet dysfunction or disseminated intravascular coagulation.

In summary, a transient and reversible imbalance of inflammatory mediators, cytokines and chemokines occurs during severe dengue, probably driven by a high early viral burden, and leading to dysfunction of vascular endothelial cells, derangement of the haemocoagulation system then to plasma leakage, shock and bleeding.

Transmission of the dengue virus

Humans are the main amplifying host of the virus.

After this extrinsic incubation period, the virus can be transmitted to other humans during subsequent probing or feeding. Thereafter the mosquito remains infective for the rest of its life.

Ae. aegypti is one of the most efficient vectors for arboviruses because it is highly anthropophilic, frequently bites several times before completing oogenesis, and thrives in close proximity to humans.

Clinical Manifestations

For a disease that is complex in its manifestations, management is relatively simple, inexpensive and very effective in saving lives so long as correct and timely interventions are instituted.

The key is early recognition and understanding of the clinical problems during the different phases of the disease, leading to a rational approach to case management and a good clinical outcome.

Febrile phase Patients typically develop high-grade fever suddenly. This acute febrile phase usually lasts 2–7 days and is often accompanied by facial flushing, skin erythema, generalized body ache, myalgia, arthralgia and headache (14).

It can be difficult to distinguish dengue clinically from non-dengue febrile diseases in the early febrile phase.

A positive tourniquet test in this phase increases the probability of dengue (15,16).

Mild haemorrhagic manifestations like petechiae and mucosal membrane bleeding

The earliest abnormality in the full blood count is a progressive decrease in total white cell count, which should alert the physician to a high probability of dengue.

14. Rigau-Perez JG et al. Dengue and dengue haemorrhagic fever. Lancet, 1998, 352:971–977. 15. Kalayanarooj S et al. Early clinical and laboratory indicators of acute dengue illness. Journal of Infectious Diseases, 1997, 176:313–321. 16 Phuong CXT et al. Evaluation of the World Health Organization standard tourniquet test in the diagnosis of dengue infection in Vietnam. Tropical Medicine and International Health, 2002, 7:125–132.

Critical phase Around the time of defervescence, when the temperature drops to 37.5–38oC or less and remains below this level, usually on days 3–7 of illness, an increase in capillary permeability in parallel with increasing hematocrit levels may occur (17,18). This marks the beginning of the critical phase.

The period of clinically significant plasma leakage usually lasts 24–48 hours.

Progressive leukopenia (15) followed by a rapid decrease in platelet count usually precedes plasma leakage.

At this point patients without an increase in capillary permeability will improve, while those with increased capillary permeability may become worse as a result of lost plasma volume.

17. Srikiatkhachorn A et al. Natural history of plasma leakage in dengue hemorrhagic fever: a serial ultrasonic study. Pediatric Infectious Disease Journal, 2007, 26(4):283– 290.

Shock occurs when a critical volume of plasma is lost through leakage. It is often preceded by warning signs. In addition, severe organ impairment such as severe hepatitis, encephalitis or myocarditis and/or severe bleeding may also develop without obvious plasma leakage or shock (19).

those who improve after defervescence are said to have non-severe dengue.

Those who deteriorate will manifest with warning signs. This is called dengue with warning signs . Cases of dengue with warning signs will probably recover with early intravenous rehydration. Some cases will deteriorate to severe dengue (see below).

19. Martinez-Torres E, Polanco-Anaya AC, Pleites-Sandoval EB. Why and how children with dengue die? Revista cubana de medicina tropical, 2008, 60(1):40–47.

Recovery phase

If the patient survives the 24–48 hour critical phase, a gradual reabsorption of extravascular compartment fluid takes place in the following 48–72 hours. General well-being improves, appetite returns, gastrointestinal symptoms abate, haemodynamic status stabilizes and diuresis ensues. Some patients may have a rash of “isles of white in the sea of red” (20). Some may experience generalized pruritus.

The haematocrit stabilizes or may be lower due to the dilutional effect of reabsorbed fluid. White blood cell count usually starts to rise soon after defervescence but the recovery of platelet count is typically later than that of white blood cell count.

“isles of white in the sea of red”

Severe dengue

Severe dengue is defined by one or more of the following:

(i) plasma leakage that may lead to shock (dengue shock) and/or fluid accumulation, with or without respiratory distress, and/or

(ii) severe bleeding, and/or

(iii) severe organ impairment.

Uniquely, the diastolic pressure rises towards the systolic pressure and the pulse pressure narrows as the peripheral vascular resistance increases. Patients in dengue shock often remain conscious and lucid. The inexperienced physician may measure a normal systolic pressure and misjudge the critical state of the patient. Finally, there is decompensation and both pressures disappear abruptly.

Severe dengue should be considered if the patient is from an area of dengue risk presenting with fever of 2–7 days plus any of the following features:

There is evidence of plasma leakage, such as: –  high or progressively rising haematocrit; –  pleural effusions or ascites; –  circulatory compromise or shock (tachycardia, cold and clammy extremities, capillary refill time greater than three seconds, weak or undetectable pulse, narrow pulse pressure or, in late shock, unrecordable blood pressure).

There is significant bleeding.

There is an altered level of consciousness (lethargy or restlessness, coma, convulsions).

There is severe gastrointestinal involvement (persistent vomiting, increasing or intense abdominal pain, jaundice).

There is severe organ impairment (acute liver failure, acute renal failure, encephalopathy or encephalitis, or other unusual manifestations, cardiomyopathy) or other unusual manifestations.

Management

Investigations

A full blood count should be done at the first visit.

A haematocrit test in the early febrile phase establishes the patient’s own baseline haematocrit.

A decreasing white blood cell count makes dengue very likely.

A rapid decrease in platelet count in parallel with a rising haematocrit compared to the baseline is suggestive of progress to the plasma leakage/critical phase of the disease..

Diagnostic criteria

Highly suggestive

IgM + in a single serum sample

IgG +in a high titre

Confirmed

PCR +

Virus culture+

IgM seroconversion in paired sera

IgG seroconversion in paired sera or 4 fold increase in titer.

Group A

These are patients who are able to tolerate adequate volumes of oral fluids and pass urine at least once every six hours, and do not have any of the warning signs, particularly when fever subsides.

Ambulatory patients should be reviewed daily for disease progression (decreasing white blood cell count, defervescence and warning signs) until they are out of the critical period:

. Adhere to the following action planEncourage oral intake of oral rehydration solution (ORS), to replace losses from fever and vomiting.

Give paracetamol for high fever if the patient is uncomfortable. The interval of paracetamol dosing should not be less than six hours. Do not give non-steroidal anti-inflammatory agents (NSAIDs)

Instruct the care-givers that the patient should be brought to hospital immediately if any of the following occur:

no clinical improvement,

deterioration around the time of defervescence,

severe abdominal pain, persistent vomiting,

cold and clammy extremities,

lethargy or irritability/restlessness,

bleeding

Admission criteria

Group B(warning signs+)

These include patients with warning signs, those with co-existing conditions that may make dengue or its management more complicated such as

pregnancy,

infancy,

old age,

diabetes mellitus,

renal failure,

chronic haemolytic diseases, and those with certain social circumstances

Without warning signs

Encourage oral fluids. If not tolerated, start intravenous fluid therapy of 0.9% saline or Ringer’s lactate with or without dextrose at maintenance rate

Group C

Patients require emergency treatment and urgent referral when they are in the critical phase of disease, i.e. when they have:

–  severe plasma leakage leading to dengue shock and/or fluid accumulation with respiratory distress; –  severe haemorrhages; –  severe organ impairment (hepatic damage, renal impairment, cardiomyopathy, encephalopathy or encephalitis).

Treatment of hemorrhage

Severe bleeding can be recognized by:

 persistent and/or severe overt bleeding in the presence of unstable

haemodynamic status, regardless of the haematocrit level;

decrease in haematocrit after fluid resuscitation together with unstable haemodynamic status;

refractory shock that fails to respond to consecutive fluid resuscitation of 40-60 ml/kg;

hypotensive shock with low/normal haematocrit before fluid resuscitation;

persistent or worsening metabolic acidosis ± a well-maintained systolic blood pressure, especially in those with severe abdominal tenderness and distension.

haematocrit of <30% as a trigger for blood transfusion, as recommended in the Surviving Sepsis Campaign Guideline (21), is not applicable to severe dengue. The reason for this is that, in dengue, bleeding usually occurs after a period of prolonged shock that is preceded by plasma leakage.

Give 5–10ml/kg of fresh-packed red cells or 10–20 ml/kg of fresh whole blood at an appropriate rate and observe the clinical response. It is important that fresh whole blood or fresh red cells are given.

21. Dellinger RP, Levy MM, Carlet JM. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Critical Care Medicine, 2008, 36:296–327.

There is little evidence to support the practice of transfusing platelet concentrates and/or fresh-frozen plasma for severe bleeding. It is being practiced when massive bleeding can not be managed with just fresh whole blood/fresh-packed cells, but it may exacerbate the fluid overload.

It should be noted that prophylactic platelet transfusions for severe thrombocytopenia in otherwise haemodynamically stable patients have not been shown to be effective and are not necessary (22).

22. Lum L et al. Preventive transfusion in dengue shock syndrome – is it necessary? Journal of Pediatrics, 2003, 143:682–684. 54

Discharge criteria

Clinical

No fever in 48 hours

Improvement in clinical status

Laboratory criteria

Increasing trend of platelet count

Stable hematocrit without iv fluid hydration

References

(1) . PAHO. Plan continental de ampliacion e intensificacion del combate al Aedes aegypti. Informe de un grupo de trabajo, Caracas, Venezuela. Abril 1997. Washington, DC, Pan American Health Organization, 1997 (Document OPS/HCP/HCT/90/97, in Spanish) (http://www.paho.org/Spanish/AD/DPC/CD/doc407.pdf)

(2)Centers for Disease Control and Prevention. Travel-associated dengue -- United States, 2005. Morbidity and Mortality Weekly Report, 2006, 55(25):700--702.

References(3)Schwartz E. Seasonality, annual trends, and characteristics of dengue among ill returned travelers, 1997–2006. Emerging Infectious Diseases, 2008, 14(7).

(4) Halstead SB, Nimmannitya S, Cohen SN. Observations related to pathogenesis of dengue hemorrhagic fever. IV. Relation of disease severity to antibody response and virus recovered. Yale Journal of Biology and Medicine, 1970, 42:311–328.

(5) Sangkawibha N et al. Risk factors in dengue shock syndrome: a prospective epidemiologic study in Rayong, Thailand. I. The 1980 outbreak. American Journal of Epidemiology, 1984;120:653--669.

(6) Guzman MG et al. Epidemiologic studies on dengue in Santiago de Cuba, 1997. American Journal of Epidemiology, 2000, 152(9):793--799.

References7. Halstead SB. Pathophysiology and pathogenesis of dengue haemorrhagic fever. In: Thongchareon P, ed. Monograph on dengue/dengue haemorrhagic fever. New Delhi, World Health Organization, Regional Office for South-East Asia, 1993 (pp 80--103).

8. Halstead SB. Antibody, macrophages, dengue virus infection, shock, and hemorrhage: a pathogenetic cascade. Reviews of Infectious Diseases, 1989, 11(Suppl 4):S830--S839.

9. Halstead SB, Heinz FX. Dengue virus: molecular basis of cell entry and pathogenesis, 25-27 June 2003, Vienna, Austria. Vaccine, 2005, 23(7):849--856.

10. Kouri GP, Guzman MG. Dengue haemorrhagic fever/dengue shock syndrome: lessons from the Cuban epidemic, 1981. Bulletin of the World Health Organization, 1989, 67(4):375--380.

References11. Sierra B, Kouri G, Guzman MG. Race: a risk factor for dengue hemorrhagic fever. Archives of Virology, 2007, 152(3):533--542.

12. Avirutnan P et al. Dengue virus infection of human endothelial cells leads to chemokine production, complement activation, and apoptosis. Journal of Immunology, 1998, 161:6338--6346.

13. Cardier JE et al. Proinflammatory factors present in sera from patients with acute dengue infection induce activation and apoptosis of human microvascular endothelial cells: possible role of TNF-alpha in endothelial cell damage in dengue. Cytokine, 2005, 30(6):359--365.

References14. Rigau-Perez JG et al. Dengue and dengue haemorrhagic fever. Lancet, 1998, 352:971–977.

15. Kalayanarooj S et al. Early clinical and laboratory indicators of acute dengue illness. Journal of Infectious Diseases, 1997, 176:313–321.

16 Phuong CXT et al. Evaluation of the World Health Organization standard tourniquet test in the diagnosis of dengue infection in Vietnam. Tropical Medicine and International Health, 2002, 7:125–132.

17. Srikiatkhachorn A et al. Natural history of plasma leakage in dengue hemorrhagic fever: a serial ultrasonic study. Pediatric Infectious Disease Journal, 2007, 26(4):283– 290.

18. Nimmannitya S et al. Dengue and chikungunya virus infection in man in Thailand, 1962–64. Observations on hospitalized patients with haemorrhagic fever. American Journal of Tropical Medicine and Hygiene, 1969, 18(6):954–971.

19. Martinez-Torres E, Polanco-Anaya AC, Pleites-Sandoval EB. Why and how children with dengue die? Revista cubana de medicina tropical, 2008, 60(1):40–47.

References

20. Nimmannitya S. Clinical spectrum and management of dengue haemorrhagic fever. Southeast Asian Journal of Tropical Medicine and Public Health, 1987, 18(3):392– 397.

21. Dellinger RP, Levy MM, Carlet JM. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Critical Care Medicine, 2008, 36:296–327.

22. Lum L et al. Preventive transfusion in dengue shock syndrome – is it necessary? Journal of Pediatrics, 2003, 143:682–684. 54