Fever, rash, and pain in the extremities of returning pediatric travelers

The Cases

Two siblings, 5-year-old Emmanuel and 3-year-old Cassandra, are brought to your emergency department (ED) in July 2014 by their parents. Both children are up to date on their immunizations and have not had significant medical problems in the past. They were referred to you by their pediatrician for 1 day of high fevers, rash, and pain in the extremities. Emmanuel had 1 episode of gum bleeding last night. His sister has been unwilling to walk since this morning.    

NEXT: What's the diagnosis?

Histories

Emmanuel began feeling ill at 6:30 am yesterday. His parents noted that he seemed irritable when being dropped off with family friends for daycare. He was very sleepy all day, refusing to play games or go outside, and had an episode of non-bloody, non-bilious emesis. When his parents picked him up yesterday afternoon, he complained of pain in his wrists, knees, and ankles. His mother noticed that he had a spotty, red rash on his extremities as well as a fever to 102⁰F, which she treated with acetaminophen. Later that evening, he had mouth pain and gum bleeding while brushing his teeth. Before going to bed, his fever had climbed to 105.8⁰F. On the morning of presentation to your ED, he is still fussy and complaining of pain in his extremities. His fever has declined slightly with acetaminophen given at home.

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Cassandra had been feeling well until yesterday evening, when she began complaining of tiredness and pain in her extremities. She refused most of her dinner and went to bed early.  She woke up at 2:45 am, inconsolably screaming in pain. This morning she developed a fever to 103.3⁰F as well as a similar blanching, red rash on her trunk and lower extremities. She has been tired and cranky, and now refuses to walk on her own, but has not had any episodes of bleeding. She received acetaminophen this morning with little improvement in her symptoms.

Further interviewing of the family revealed that both patients spent the past month in Haiti with their father, visiting friends and relatives, and returned home to the United States 3 days prior to presentation. Similar to previous visits, the children got no pre-travel immunizations; took no anti-malarial prophylaxis; and did not sleep under bed nets (as per the culture in this upper economic class, highland area of Haiti). Both children occasionally drank unfiltered water from street vendors, swam at the public beach, and played with domestic pets. Their father also reports having had fever, joint pain, and bleeding from the gums a week prior to leaving Haiti, which have since resolved.

Physical examinations

Emmanuel is alert and responsive, lying unhappily on the exam table. He cries when his father moves him for you to examine better. His temperature is 103.6⁰F, heart rate 130, respiratory rate 28, and blood pressure 106/59 mm Hg. There is a clearly visible erythematous, maculopapular rash, mainly on his face and extremities, including his palms and soles, in addition to numerous mosquito bites. His sclerae are slightly injected, and there is minimal dried blood behind his upper central incisors. There is no meningismus. You detect a grade 1-2 systolic murmur along the left sternal border. Otherwise, pulmonary, abdominal, and neurological exams are unremarkable. His extremities are not swollen or tender to palpation, and you can passively move his joints fully.

Initially, Cassandra appears exhausted in her mother’s arms. She clings to her as you begin your examination, but seems too worn out to complain. Her temperature is 103.3⁰F, heart rate 146, respiratory rate 44, and blood pressure 114/74 mm Hg. She has a faint erythematous, maculopapular rash on her face, trunk, and extremities, as well as many scattered mosquito bites. Her sclerae are injected, and she has diffuse cervical lymphadenopathy. There is no meningismus. There is a grade 1-2 systolic murmur heard best along the left sternal border. Pulmonary, abdominal, and neurological exams are otherwise unremarkable. Her joints are not swollen and do not seem tender on passive movement.

NEXT: Differential diagnosis

Differential diagnosis

Given the familial triad of symptoms, an infectious source or common exposure is most likely.  In returning travelers from Haiti, it is important to consider both infectious diseases more commonly seen in clinics in the continental United States, as well as the more “exotic,” for example, dengue, malaria, and typhoid fever (Table).^1-10 Historically, a child presenting in the summer with high fever and unwillingness or inability to walk would have raised alarms for polio. Thankfully, polio virus has not returned to the western hemisphere. However there is another possible viral cause for a patient returning from Haiti with this presentation, which you wouldn’t have included in your differential diagnosis before 2013.

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NEXT: Testing and treatment

ED testing and treatment

Emmanuel’s white blood cell (WBC) count is 6000 cells/mm³, with a differential of 3% metamyelocytes, 5% bands, 80% neutrophils, 4% lymphocytes, 4% atypical lymphocytes, and 4% monocytes; hemoglobin (Hb) is 12.2 g/dL; and platelet count is 182,000 cells/mm³. His bicarbonate is slightly low at 20 mEq/L, aspartate aminotransferase minimally elevated at 43 units/L, and creatine kinase normal at 106 units/L.

Cassandra’s WBC count is 8280 cells/mm³, with a differential of 2% bands, 83% neutrophils, 9% lymphocytes, 5% atypical lymphocytes, and 1% monocytes; Hb is 12.5 g/dL; and platelet count is 219,000 cells/mm³. Her sodium, 131 mEq/L, and bicarbonate, 18 mEq/L, are low.

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Both children’s urinalyses are essentially normal. Their rapid strep screens are negative.

In the ED, Emmanuel and Cassandra are given acetaminophen and intravenous fluids to help manage their symptoms. Thick and thin Giemsa blood smears show no malaria parasitemia, leading you to conclude that the infection, exotic as it may be, is most likely viral and should resolve with supportive care. Several hours after receiving treatment, their vital signs return to normal, and both children are deemed safe to be discharged home, with a warning to the parents not to administer aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) until dengue is ruled out.

One week later, the ‘send out’ tests return showing positive chikungunya virus RNA by reverse transcription polymerase chain reaction (RT-PCR). Blood cultures and dengue PCRs are negative.

Discussion

Chikungunya is an arbovirus (arthropod-borne virus) of the family Togaviridae and genus Alphavirus, related to other alphaviruses such as Western equine encephalitis virus and Venezuelan equine encephalitis virus.¹¹ The virus’s name comes from the Makonde word for “walking bent over,” reflecting the painful musculoskeletal symptoms of the disease.¹² The primary vectors for the virus during human epidemics are female Aedesaegypti and Aedes albopictus mosquitoes, both of which can also transmit dengue.^12-15 The greatest risk of transmission from Aedes mosquitoes occurs during the daytime-in contrast to malaria-transmitting Anopheles mosquitoes, which tend to be more active at dusk, dawn, or overnight.  Historically, chikungunya was localized to the Old World (it is endemic mainly in sub-Saharan Africa and South and East Asia), and, in fact, primary infections were not seen in the western hemisphere until late 2013.^13,16 While initially reported in the French part of the isle of St Martin, the virus has spread rapidly throughout the Caribbean, affecting more than a million people in total.^16,23 Infections appear to have peaked there in July 2014, with over 250,000 infections in that month alone.^21,22 Chikungunya fever has taken a particular heavy toll in Haiti, where poor mosquito vector control since the 2010 earthquake has led to hundreds of thousands of cases. Since recurrent infection does not occur, with time, a sufficient number of persons in a local population will develop immunity and help contain widespread transmission.¹⁵

Most infections become symptomatic.^12,15 Infection is usually followed by a typical incubation period of 3 to 7 days (range, 1-12 days).¹⁵ Chikungunya initially infects monocytes, leading to a large type I-interferon release and the acute-onset of fever (typically >102.2⁰F), rigor, and shivering.^12,14,15 Polyarthralgia follows.^12,14,15 Sometimes there is articular or periarticular swelling, usually without redness or warmth. Joint manifestations are often symmetrical and migratory. Peripheral joints (fingers, wrists, elbows, toes, ankles, knees) are most commonly affected, although other joints (proximal extremity, axial skeleton) are frequently involved, too. The pain can be disabling, rendering many patients nonambulatory for several days. A macular or maculopapular, sometimes erythematous, rash often develops during the first week of symptoms.^12,14,15 Bullous or vesicular lesions can occur, more commonly in infants.^12,17 Additional clinical manifestations may include headache, conjunctivitis, gastrointestinal symptoms, myalgias, and lymphopenia.^12,14,15 Life-threatening complications have been reported, but seem to be less common in children (non-newborns).^12,14,15 While the acute disease process rarely lasts more than a week to 10 days, residual arthralgia, arthritis, and/or tenosynovitis can persist for months or even years, particularly in the elderly and adults with comorbidities such as diabetes and impaired renal function.^12,14,15

NEXT: What is chikungunya mistaken for?

Chikungunya is often mistaken for other tropical infections, most commonly dengue fever.^{12,14-16,18,19} In chikungunya infection, fever tends to resolve within 3 to 5 days (range, 1-10 days), while, in dengue, it may persist a little longer. Further, the polyarthralgia/polyarthritis seen in chikungunya are less common in dengue; in dengue, the musculoskeletal symptoms are more commonly described as myalgias. Retro-orbital pain, classically described with dengue, is rarely seen in chikungunya; in chikungunya, conjunctivitis occurs not infrequently. Lastly, hemorrhagic manifestations (thrombocytopenia, bleeding gums, etc) are possible in chikungunya, but are much more commonly seen in dengue fever. Dengue hemorrhagic shock syndrome is rarely, if ever, caused by chikungunya.

Diagnosis of chikungunya begins by eliciting a thorough travel and exposure history.  Families visiting foreign friends and relatives are often at increased risk for travel-related infections for a variety of reasons. As in this case, foreign residents and their visiting family often do not take sufficient preventive precautions.²⁰ Laboratory testing is essential to differentiate this illness from malaria and typhoid fever, which can be treated with antibiotics. Testing is performed with thick and thin smears and blood and stool cultures for malaria and typhoid fever, respectively. Malaria rapid diagnostic tests may be particularly useful in some ED settings. Although chikungunya and dengue virus PCR tests are ideal for diagnosis during the viremic phase of disease, serologic testing for immunoglobulin M (IgM) and immunoglobulin G antibodies may be simpler, faster, and less expensive for some clinical laboratories.^12,14,15,19 Chikungunya RNA levels become negligible by the 5th to 8th day after onset of symptoms.^12,14,15,19 The IgM antibodies are detectable around the 5th day.^12,14,15,19 Also, serologic testing is useful to look for the presence of preexisting anti-dengue virus antibodies, which can predispose patients to dengue hemorrhagic shock syndrome if they are infected with a second dengue serotype.

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No specific antiviral agent is proven to be effective in vivo against chikungunya.^12,14-16,18 Treatment for both chikungunya and dengue is primarily supportive.^12,14,15,18 Aspirin and NSAIDs should not be used for pain relief or as an antipyretic in dengue due to the potential for thrombocytopenia and hemorrhage.^18,19 Thrombocytopenia occurs less frequently in chikungunya.^14,15,18

There is no commercially available vaccine to prevent chikungunya disease, despite research to develop one.^12,14-16,19 Similar to dengue and malaria, methods to minimize mosquito bites are the mainstays of prevention, as well as of reducing further spread.^14-16,19,20

Outcome

One week after presenting to your ED with symptoms and signs of acute chikungunya virus infection, Emmanuel and Cassandra’s parents are contacted with the positive test results. They report that both children are now doing fine, and are just as active as before their illnesses.

Reporting of chikungunya cases became mandatory in 2015.¹⁵ Cases should be reported to the state or local health department.^15,19 The State Department of Health is notified about Emmanuel and Cassandra, but is not concerned about tracing contacts.

References

1.     Centers for Disease Control and Prevention. Malaria diagnosis and treatment in the United States. http://www.cdc.gov/malaria/diagnosis_treatment/. Accessed September 24, 2015.

2.     Centers for Disease Control and Prevention. Dengue and dengue hemorrhagic fever. http://www.cdc.gov/dengue/resources/Dengue&DHF%20Information%20for%20Health%20Care%20Practitioners_2009.pdf. Accessed September 24, 2015.

3.     Lee VJ, et al. Simple clinical and laboratory predictors of Chinkungunya versus dengue infections in adults. PLoS Negl Trop Dis. 2012;6(9):e1786.

4.     Centers for Disease Control and Prevention. Typhoid fever. http://www.cdc.gov/nczved/divisions/dfbmd/diseases/typhoid_fever/

5.     Hohmann EL. UpToDate. Epidemiology, microbiology, clinical manifestations, and diagnosis of typhoid fever. http://www.uptodate.com/contents/epidemiology-microbiology-clinical-manifestations-and-diagnosis-of-typhoid-fever. Accessed September 24, 2015.

6.     Hohmann EL. UpToDate. Treatment and prevention of typhoid fever. http://www.uptodate.com/contents/treatment-and-prevention-of-typhoid-fever. Accessed September 24, 2015.

7.     DermNet NZ. Leptospirosis. http://www.dermnetnz.org/bacterial/leptospirosis.html. Accessed September 24, 2015.

8.     Gompf SG. Leptospirosis. Medscape. Updated April 14, 2015. http://emedicine.medscape.com/article/220563. Accessed September 24, 2015.

9.     Pavli A, Maltezou HC. Travel-acquired leptospirosis. J Travel Medicine. 2008;15(6):447-453.

10.  Akhter K. Relapsing fever treatment and management. Medscape. Updated December 10, 2014. http://emedicine.medscape.com/article/227272-treatment. Accessed September 24, 2015.

11.  Griffin DE. Alphaviruses. In: Knipe DM, Howley PM, eds. Fields Virology. 6^th ed. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins; 2013:651-86.

12.  Chia PY, Ng MML, Chu JJH. Chikungunya fever: a review of a re-emerging mosquito-borne infectious disease and the current status. In: Mendez-Vilas A, ed. Current Research, Technology and Education Topics in Applied Microbiology and Microbial Technology. Badajoz, Spain: Formatex Research Center; 2010:597-606.

13.  Khan K, Bogoch I, Brownstein JS, et al. Assessing the origin of and potential for international spread of chikungunya virus from the Caribbean. PLoS Curr. 2014 Jun 6;6:ecurrents.outbreaks.2134a0a7bf37fd8d388181539fea2da5.

14.  Wilson ME. Chikungunya fever. In Hirsch MS, Baron EL, eds. UpToDate. Alphen aan den Rijn, Netherlands: Wolters Kluwer; 2015.

15.  Centers for Disease Control and Prevention. Chikungunya virus. http://www.cdc.gov/chikungunya/hc/index.html. Accessed April 23, 2015.

16.  Centers for Disease Control and Prevention. First reports of chikungunya in western hemisphere. http://www.cdc.gov/media/releases/2013/p1218-chikungunyas.html. Published December 18, 2013. Accessed July 15, 2015.

17.  Seetharam KA, Sridevi K, Vidyasagar P. Cutaneous manifestations of chikungunya fever. Indian Pediatr. 2012;49(1):51-53.

18.  Centers for Disease Control and Prevention. Chikungunya: clinical management in dengue-endemic areas. http://www.cdc.gov/chikungunya/pdfs/CHIKV_DengueEndemic.pdf. Accessed June 30, 2015.

19.  Sharp TM. Differentiating chikungunya from dengue: a clinical challenge. http://www.medscape.com/viewarticle/831523. Published September 15, 2014. Accessed June 23, 2015.

Bacaner N, Stauffer B, Boulware DR, Walker PF, Keystone JS. Travel medicine considerations for North American immigrants visiting friends and relatives. JAMA. 2004;291(23):2856-2864.

Pan American Health Organization. “Number of Reported Cases of Chikungunya Fever in the Americas – EW26.” Chikungunya: Statistic Data. http://www.paho.org/hq/index.php?option=com_topics&view=readall&cid=5927&Itemid=40931&lang=en . Accessed August 10, 2015.

Pan American Health Organization. “Number of Reported Cases of Chikungunya Fever in the Americas – EW31.” Chikungunya: Statistic Data. http://www.paho.org/hq/index.php?option=com_topics&view=readall&cid=5927&Itemid=40931&lang=en . Accessed August 10, 2015.

Pan American Health Organization. “Number of Reported Cases of Chikungunya Fever in the Americas – Cumulative Cases (May 15, 2015).” Chikungunya: Statistic Data. http://www.paho.org/hq/index.php?option=com_topics&view=readall&cid=5927&Itemid=40931&lang=en . Accessed August 10, 2015.