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A CASE STUDY OF FEVER IN THE EXPATRIATE

(Compiled by Dr Jonathan Klotnick)

Mr Christopher is a 59 year old socio-economic consultant who has been working in the Philippines for the past six years. He consults to rural communities and travels occasionally from the urban city of Manila to the rural areas. He spends one to two nights consulting to the community leaders and then returns to the city. He has no contact with any animals although does see rodents in the areas where he stays.

He is a well patient with no significant medical history. He is not on any chronic medication and has no known allergies. He reports to have had multiple vaccinations in the past for various diseases, however he cannot find his vaccination card.

                             

On Saturday morning 8/7/2012 he felt unwell, took his own temperature and noticed a fever of 38.6oC. He felt he did not want to be seen by medical doctors in the Philippines and he returned to South Africa that night and consulted a doctor the following morning (Sunday 9/7/2012). His symptoms were of a fever and “sinusitis”- discomfort in his sinuses and a post nasal drip with ‘thicker mucous than the previous day’.

Questions:

1.     What is the differential diagnosis?

2.     What examinations, if any, would one do?

3.     Assuming this is sinusitis, what would be the best treatment at present?

4.     Is Manila a high-risk malaria area?

5.     What malaria species have been reported in the Philippines?

Answers:

1.      The differential diagnosis includes common illnesses such as: sinusitis-viral or bacterial, infected post-nasal drip, flu or ENT viruses. The other differential diagnoses that need to be considered are those that he may have encountered in the area in which he was living, such as: Malaria, other viruses, possible early symptoms of other tropical diseases etc.  

 

2.      First, would be to examine the patient for clinical clues of the diagnosis ie. Vital signs, thorough general examination viz. ENT, Cardiac, Respiratory, Abdominal, Neurological, Urinary (including a urine dipstix) and dermatological examination.

3.      Should this be sinusitis, the treatment at the moment could involve symptomatic treatment for now eg. Nasal spray and decongestants or antihistamines. Observation and re-examine should the symptoms worsen.

 

4.     Areas of the Philippines with Malaria: Present in rural areas <600 m (1,969 ft) on the islands of Luzon, Mindanao, Mindoro, and Palawan. None in urban areas, thus no malaria in Manilla, however our patient did visit rural areas on numerous occasions

 

 

5.     The Malaria species found in the Philippines are approximately 75% Plasmodium Falciparum and 25% Plasmodium Vivax.

 

 

The GP on the Sunday morning in Johannesburg prescribed Moxifloxacin for the sinusitis and did blood tests (see summary of blood tests table dated 9/7/2012). The blood test for malaria parasites was requested, which was negative. He was told the rest of the blood tests were normal and that his symptoms were sinus related. NB! As we can see (bloods done on the 9/7/2012) were not all normal as the GP had told the patient, his platelet count was abnormal- decreased!

Questions:

1.     Is an antibiotic indicated for sinusitis?

2.     Is moxifloxacin an appropriate first line antibiotic for sinusitis?

3.     Is the GP’s communication to the patient appropriate?

Answers:

1.     Without getting into too much detail, sinus infections usually resolve spontaneously with or without symptomatic treatment. The use of antibiotics to treat sinusitis within the first week is questionable and studies have shown that they should only be prescribed after 7 days of symptomatic sinusitis.

2.     The above patient did not have any allergy to penicillin and perhaps the use of moxifloxacin as a first line treatment for the sinusitis may have been an inappropriate choice of antibiotic. A penicillin based antibiotic such as Amoxicillin or Augmentin would have been more appropriate.

3.     The GP reported to the patient that his test results were normal when there was an abnormality present. The GP did not discuss any follow-up plans. It is of utmost importance to discuss the possible outcomes of the diagnosis made by the GP and to discuss what other possible symptoms may occur or the patient may experience. For the sake of the patient’s wellbeing this is most important and secondly in todays world of medicine the aspect of litigation is a real concern. This however will not be discussed further but to say that by spending an extra 3-5mins with a patient and communicating to them and allowing them to ask questions about their disorder and its course, could significantly reduce the incidence of litigation.

He consulted the practice on 11 July 2012 for a second opinion as his fever and malaise were persisting. He was still on moxifloxacin for his sinus symptoms.  He had a sore throat and his sinuses felt inflamed. He was nauseous and was retching. There was no diarrhoea, no skin rashes and the patient reported no history of mosquito bites. As we know, many patients report not having been bitten by mosquitos, but we know bites may not itch, they may be concealed eg. scalp and some people may not mount a reaction to mosquito bites. He had no swollen glands, no myalagia or arthralgia and he was not confused. His urine was of a normal colour and there was no suggestion of a urinary tract infection.

On examination he was pyexial (38.3 oC) and fully orientated. There was no rash, no neck stiffness, no lymphadenopathy. His cardiac and respiratory examinations were normal. There was no hepatosplenomegaly and central nervous system examination was normal. Clinically the sinus symptoms were not severe but persisting.

Further blood tests were done (see Table of blood tests done 11/07/2012). Of significance was the rapid drop in platelets, low lymphocytes and neutrophils and stable haematocrit. The repeat malaria was negative. The liver function tests were slightly more deranged than previously.

 

QUESTIONS

1.     What are the recent disease risks for travelers to the Philippines?

2.     What differential diagnoses should now be entertained?

ANSWERS

1.      An outbreak of leptospirosis was reported from the Philippines in July 2011 after widespread flooding, causing more than 2000 cases and 156 deaths by October, chiefly in Western Visayas, National Capital Region, Central Luzon, and Davao. A fresh outbreak was reported in January 2012 from the island of Mindanao, after flooding caused by tropical storm Washi (see ProMED mail, July 16 and October 18, 2011, and January 14, 2012).In October 2009, a leptospirosis outbreak occurred after two tropical storms hit the island of Luzon within several days of each other. As of October 26, a total of 2158 cases and 167 deaths had been identified, chiefly in Metro Manila and Rizal Province (see ProMED- mail, October 16 and 23, 2009). In June 2008, an increased incidence of leptospirosis was noted in the Davao Region (see ProMED mail, June 26, 2008).

An outbreak of schistosomiasis was reported from Palo, Leyte, in June 2011, causing almost 100 cases. The outbreak appeared to have been caused by floods (see ProMED mail, June 11, 2011).

A malaria outbreak was reported in July 2010 from Camarines Norte province in southeastern Luzon, causing 182 cases, chiefly in Jose Panganiban town. In August 2010, a malaria outbreak was reported from the province of Rizal, chiefly involving the remote and upland villages of Taytay municipality (see ProMED mail, July 27 and August 8, 2010). In January 2010, a malaria outbreak was reported from North Cotabato (Mindanao), causing at least 43 cases by April (see ProMED mail, April 24, 2010).

A series of measles outbreaks were reported from the Philippines in the first four months of 2010, chiefly affecting the National Capital Region (NCR), Calabarzon, Ilocos, Central Luzon and Bicol. Almost 2000 cases were reported nationwide, almost five times as many as during the same period the previous year. In the first three months of 2011, more than 2000 cases of measles were reported nationwide, including five fatalities. The majority of the cases were in the National Capital Region, followed by Central Luzon, Bicol region, Calabarzon, Davao region, Ilocos region, and Zamboanga peninsula. A measles outbreak was reported from Capiz in July 2011.

Outbreaks of Dengue fever, a flu-like illness which may be complicated by hemorrhage or shock, are reported regularly from the Philippines. More than 45,000 cases were reported nationwide for the first seven months of 2011, more than half of them from Luzon. The most recent outbreaks were reported in October 2011 from Aklan province, in August 2011 from Metro Manila, Central Luzon, Quezon City, La Union province, and Eastern Visayas, and in July 2011 from Pampanga province, Kalinga province, Batanes, Cordillera Administrative Region, southwestern Mindanao, and Laoag city, Ilocos Norte province. An unusually large number of cases were reported in 1998, possibly related to climatic changes due to El Nino. Fewer cases were reported in 1999 and 2000, but the numbers began to rise again in 2001.

Rabies is a problem in the Philippines. More than 200 human deaths from rabies were reported nationwide in the first 10 months of 2010. A rabies outbreak was reported among dogs in Negros Occidental in August 2010, leading to one fatal human case. A total of 250 human cases were reported in the year 2009, chiefly from Luzon, Mindanao, and Visayas. A rabies outbreak related to unvaccinated dogs was reported in September 2007 from Bauang, La Union Province, causing three deaths.

Outbreaks of typhoid fever are frequently reported from the Philippines, most recently from Cebu Province in March 2012 and Leyte Province in January 2012. In November 2008, a suspected outbreak was reported from the towns of Real and Infanta, Quezon province. In March 2008, a typhoid outbreak was reported from Iloilo City, the capital of Iloilo province in the Western Visayas region. In February 2008, an outbreak was reported from Calamba City in Laguna province, about 30 miles south of Manila, resulting in almost 2000 cases by March. Also in February, an outbreak was reported from a mountain town in the eastern part of the province of Nueva Vizcaya, located in the Cagayan Valley region on Luzon. In January 2008, typhoid outbreaks were reported from a remote village in the municipality of Bayombong, capital of Nueva Vizcaya province, and from the village of Kisulad in the province of Davao del Sur.

Cholera outbreaks occur regularly in the Philippines. The most recent were reported in April 2011 from Palawon; in August 2010 from barangay Vitali in Zamboanga; in January 2009 from Ticao Island, Masbate, Bicol; in November 2008 from the settlement of Tagoloan in southern Misamis Oriental; in September 2008 from Pangasinan province on the island of Luzon; and in August 2008 from two tribal communities in Palimbang, Sultan Kudarat. Most travelers are at extremely low risk for infection.

 

1.     Differential diagnoses

·         Malaria

·         Viral Hepatitis

·         Other viruses eg. EBV

·         Dengue Fever

·         Acute Leukaemia

·         Typhoid Fever

·         Leptospirosis

·         Acute HIV seroconversion

 

QUESTIONS

 

1.     What other infections can cause a thrombocytopaenia?

 

2.     Could there be antibiotic induced thrombocytopaenia?

ANSWERS

1.     Malaria, EBV, Toxoplasmosis, cytomegalovirus, HIV, viral haemorragic fever viruses, Dengue Fever.

Sepsis/ infection due to the following bacteria or viruses can cause thrombocytopaenia viz. Rubella virus, HIV, Staphylococcus sp., Enterococcus sp.,Listeria monocytogenes, Escherichia coli, Haemophilus influenzae,Klebsiella pneumoniae,Pseudomonas aeruginosa, Candida species.

2.     The antibiotics usually responsible for antibiotic induced thrombocytopaenia are: Penicillins, Cephalosporins and Sulphonamides. The antibiotic moxifloxacin is a quinolone antibiotic and quinonlones are not usually a cause of thrombocytopaenia.

 

 12/07/12

The patient returned for follow-up:

Clinically: T=38.4 oC ,mild petechial rash on lower limbs, red flushing on back . A ’saccule’ at back of pharynx was noted at all examinations. This saccule was of a blood-stained colour. Examination of the cardiovascular, respiratory, gastro-intestinal and central nervous system was normal. . Urine dipstix test was normal, urine was not sent to the laboratory for analysis. There was no bleeding from any sites.

Questions:

1.     What is the most likely diagnosis?

2.     What precautions should be taken to prevent spread, if this was a Viral Haemorrhagic Fever, to other patients with whom he came into contact in the doctors rooms?

3.     What steps should be taken if the patient is not admitted to hospital?

 

Answers:

1.      Dengue Fever

2.     To make note of who was in the waiting room at the time he was seen. Minimise his exposure to others by ensuring, on arrival at the surgery, to have him taken into a side room or examination room immediately. Basic health precautions to avoid body fluids contact such as gloves and face masks should be used especially if patient was vomiting or bleeding.

3.     To remain in constant contact should his clinical picture change or should any spontaneous bleeding take place. His wife was also going to be with him and observing him for any changes. If the patient is close to a hospital and good communication between doctor and patient is maintained, that the patient had no other co-morbid diseases, that there is some other person around to observe or assist, then it may suffice to manage the patient as an out-patient.

 

Bloods were sent to the NICD special pathogens unit.

13/07/12

The patient felt better and was apyrexial but the rash was now more prominent on the lower limbs. The NICD results confirmed Dengue virus infection.

 

Summary of Blood tests of the case:

 

09/07/2012

11/07/2012

12/07/2012

14/07/2012

17/07/2012

22/07/2012

 
 

Day 1

Day 3

Day 4

Day 6

Day 9

Day 14

normal values

               

Haemoglobin

14.9

15.3

 

15.5

15.5

13.8

13.8-18.8

WCC

1.9

1.24

1.61

2.67

3.08

5.46

4.0-12.0

Neutrophils

1.06

0.62

0.95

1.04

1.65

2.9

2.0-7.5

Lymphocytes

0.35

0.38

0.41

1.23

0.63

1.36

1.0-4.0

Eosinophils

0.01

0.01

0.02

0.03

0.05

0.08

0.0-0.5

Basophils

0.01

0.01

0

0

0.01

0.04

0.0-0.3

Monocytes

0.47

0.22

0.23

0.37

0.74

1.08

0.2-1.0

Platelets

127

94

71

65

188

309

150-450

Haematocrit

0.41

0.42

 

0.44

0.44

0.39

0.40-0.56

               

Urea

 

5.2

   

5.4

 

2.1-2.7

Creatiniine

 

98

   

81

 

80-115

ALT

39

60

 

103

85

82

<40

AST

45

99

 

125

73

51

15-40

LDH

     

338

   

120-230

ALK Phos

88

93

 

89

93

102

53-128

GGT

108

116

 

135

173

168

0-64

Bilirubin conj.

3

       

3

1.0-7.0

Bilirubin total

10

       

10

2.0-26.0

               

EBV IgM

NEG

NEG

         
               

CRP

4.8

1.4

       

<5

ESR

2

2

 

2

   

1.0-45.0

Malaria

NEG

NEG

         

blood cultures

   

negative

       

 

Questions

 

1.     What is the global spread of dengue fever?

2.     What are the different serotypes of Dengue fever and does a patient get life-long immunity after surviving Dengue?

3.     What is the vector for dengue and where is it found?

4.     What clinical signs would alert a person to the diagnosis of Dengue?

5.     What methods should be adopted to reduce the spread of Dengue?

6.     Are adults more affected than children?

7.     What is severe Dengue and is there specific treatment?

8.     Is there a vaccine for Dengue?

9.     What advice should be given to this person who is returning to Manila?

Answers

1. The incidence of dengue has increased dramatically around the world in recent decades.(Ref 4) Over 2.5 billion people – 40% of the world's population – are now at risk from dengue. WHO currently estimates there may be 50–100 million dengue infections worldwide annually. Severe dengue (previously known as Dengue Haemorrhagic Fever) was first recognized in the 1950s during dengue epidemics in the Philippines and Thailand. Today, severe dengue affects most Asian and Latin American countries and has become a leading cause of hospitalization and death among children in these regions.(Ref 9)

Before 1970, only nine countries had experienced severe dengue epidemics. The disease is now endemic in more than 100 countries in Africa, the Americas, the Eastern Mediterranean, South-east Asia and the Western Pacific. South-east Asia and the Western Pacific regions are the most seriously affected.

Cases across the Americas, South-east Asia and Western Pacific have exceeded 1.2 million cases in 2008 and over 2.2 million in 2010 (based on official data submitted by Member States). Recently the number of reported cases has continued to increase. In 2010, 1.6 million cases of dengue were reported in the Americas alone, of which 49 000 cases were severe dengue.(Ref 14)

Not only is the number of cases increasing as the disease spreads to new areas, but explosive outbreaks are occurring.(Ref 16&17) The threat of a possible outbreak of dengue fever now exists in Europe and local transmission of dengue was reported for the first time in France and Croatia in 2010 and imported cases were detected in three other European countries.(ref 10)

2.   There are four distinct, but closely related, serotypes of the virus that cause dengue (DEN-1, DEN-2, DEN-3 and DEN-4). Recovery from infection by one provides lifelong immunity against that particular serotype. However, cross-immunity to the other serotypes after recovery is only partial and temporary. Subsequent infections by other serotypes increase the risk of developing severe dengue.(Ref 18)

3. The Aedes aegypti mosquito is the primary vector of dengue. The virus is transmitted to humans through the bites of infected female mosquitoes. After virus incubation for 4–10 days, an infected mosquito is capable of transmitting the virus for the rest of its life.

Infected humans are the main carriers and multipliers of the virus, serving as a source of the virus for uninfected mosquitoes. Patients who are already infected with the dengue virus can transmit the infection (for 4–5 days; maximum 12) via Aedes mosquitoes after their first symptoms appear.

The Aedes aegypti mosquito lives in urban habitats and breeds mostly in man-made containers. Unlike other mosquitoes Ae. aegypti is a daytime feeder; its peak biting periods are early in the morning and in the evening before dusk. Female Ae. aegypti bites multiple people during each feeding period. (ref 13)

Aedes albopictus, a secondary dengue vector in Asia, has spread to North America and Europe largely due to the international trade in used tyres (a breeding habitat) and other goods (e.g. lucky bamboo). Ae. albopictus is highly adaptive and therefore can survive in cooler temperate regions of Europe. Its spread is due to its tolerance to temperatures below freezing, hibernation, and ability to shelter in microhabitats.

4.    Dengue should be suspected when a high fever (40°C/ 104°F) is accompanied by two of the following symptoms: severe headache, pain behind the eyes, muscle and joint pains, nausea, vomiting, swollen glands or rash. Symptoms usually last for 2–7 days, after an incubation period of 4–10 days after the bite from an infected mosquito.

5. At present, the only method to control or prevent the transmission of dengue virus is to combat vector mosquitoes through (Ref 6)

·         preventing mosquitoes from accessing egg-laying habitats by environmental management and modification;

·         disposing of solid waste properly and removing artificial man-made habitats;

·         covering, emptying and cleaning of domestic water storage containers on a weekly basis;

·         applying appropriate insecticides to water storage outdoor containers;

·         using of personal household protection such as window screens, long-sleeved clothes, insecticide treated materials, coils and vaporizers;

·         improving community participation and mobilization for sustained vector control;

·         applying insecticides as space spraying during outbreaks as one of the emergency vector control measures;

·         active monitoring and surveillance of vectors should be carried out to determine effectiveness of control interventions.

6. An estimated 500 000 people with severe dengue require hospitalization each year, a large proportion of whom are children. About 2.5% of those affected die.(Ref 1,2,3)

7. Severe dengue is a potentially fatal infection due to plasma leakage, fluid accumulation, respiratory distress, severe bleeding, or organ impairment. Warning signs occur 3–7 days after the first symptoms in conjunction with a decrease in temperature (below 38°C/ 100°F) and include: severe abdominal pain, persistent vomiting, rapid breathing, bleeding gums, fatigue, restlessness, blood in vomit.(Ref 11&12) The next 24–48 hours of the critical stage can be lethal: proper medical care is needed to avoid complications and risk of death. Changes in the haematocrit are known to predict for severity of the disease. In the case presented above, the patient’s haematocrit remained stable which in this case predicted for recovery and not severe Dengue.

 

There is no specific treatment for dengue fever.

For severe dengue, medical care by physicians and nurses experienced with the effects and progression of the disease can save lives – decreasing mortality rates from more than 20% to less than 1%. Maintenance of the patient's body fluid volume is critical in severe dengue care

8. There is no vaccine to protect against dengue. Developing a vaccine against dengue/ severe dengue has been challenging although there has been recent progress in vaccine development.(Ref 7&8) WHO provides technical advice and guidance to countries and private partners to support vaccine research and evaluation. Several candidate vaccines are in various phases of trials. (Ref 15)

9.The patient was told to buy bed nets, mosquito sprays and to take all protective measures to prevent mosquito bites wherever he travelled in the Philippines. He was told that there may not be lifelong protection as there were other serotypes of Dengue

 

REFERENCES AND RESOURCES:

1)Ranjit s,Kissoon N (July 2010). “Dengue haemorrhagic fever and shock syndrome”. Paediatr Crit. Care Med. 12(1):90-100

2)Varatharaj A (2010). “Encephalitis in the clinical spectrum of Dengue infection” Neuro India 58(4):585-91

3) Simmons CP, Farrar JJ, Nguyen W, Wilt B (April 2012). “Dengue”. N Engl J. Med. 366(15):1423-32

4) WHO (2009) page 3.

5) WHO (2009) page 137

6) Global strategy for dengue prevention and control. WHO 2012 pp 16-17

7) Webster DP, Farrar J, Rowland JS (Nov 2009).” Progress towards a Dengue vaccine”. Lancet Infect Dis.9 (11) 678-87

8)Guy B, Barrere B, Malinowskic C,Saville M, Teyssou R, Lang J (23 Sept 2011) “ from research phase 3 preclinical, industrial and clinical development of the Sanofi Pasteur tetravalent dengue vaccine”. Vaccine 25(42):7229-41

9)Gubler “(2010) pp 377

10) Reiter P (11 March 2010) “ Yellow Fever and Dengue: a Threat to Europe” Euro surveill 15(10):19509

11) WHO (2009) p25

12)Chen LH, Wilson ME (October 2010)” dengue and chikungunya infections in travelers” Curr Opin. Infect. Dis 23(5) 438-44

13) Farrar J, Focks D, Gubler D, Barrera R,Guzman MG, Simmons C (2007)WHO/TDR Dengue scientific working group, towards a global Dengue research agenda. Tropical Medicine and International Health. June 12 (6) 695-699

14) www.cdc.gov

15)Halstead SB, Deen J,”the future of dengue vaccines”. Lancet 2002. 30:1243-5

16) Jelinek T, et al. Epidemiology and clinical features of imported dengue fever in Europe. Clin Infect Dis 2002;35:1047-52

17)  Guzman MG, Halstead SB, Aartsob H, et al. (December 2010). “dengue a continuing global threat”. Nat. Rev. Microbio 8(12 suppl)  S7-S16

18) Das S, Pinyte MR, Munoe-Jordan JL, Rundell MS, et al(2008). Detection and serotyping of dengue virus in serum samples by multiple reverse transcriptase PCR-ligase detection assay. J. Clin. Microbiology 46: 3276-3284