Tropical Medicine 3: Fever and Systemic Manifestations
Fever may be a symptom of both infectious and non-infectious processes. This chapter focuses on those conditions for which fever is the principle, or sole, presenting symptom.
Malaria
This disease is spread through the bite of the Anopheles mosquito. When an infected mosquito takes a blood meal from a human, it injects sporozoites from its salivary glands. These infect the liver and mature to schizonts within the hepatocytes, which are released from the hepatocytes as merozoites. The merozoites infect erythrocytes and form trophozoites and develop to schizonts, which either lyse the erythrocytes as merozoites or form gametes (which undergo sexual reproduction after being taken up by the next mosquito).
Complicating this, some of the original sporozoites may form hypnozoites in the liver, which remain dormant for some time before undergoing schizogony.
In addition to the loss of RBCs due to the parasites’ lysis, other factors contribute to the pathophysiology of malaria. Parasitized RBCs exhibit altered flow characteristics, including cytoadherence, sludging, endothelial injury, and resultant hemorrhage. The production of cytokines and tumor necrosis factor (TNF) may lead to severe illness with multiple organ failure.
Four forms of the plasmodium parasite cause disease in humans, each of which produces a somewhat distinct clinical course. These are summarized in the following table.
Forms of Malaria
| Plasmodium species | falciparum |
vivax |
ovale |
malariae |
| Severity | Malignant form |
Benign |
Benign |
Benign |
| Recrudescent (do hypnozoites form) |
no |
yes |
yes |
no |
| Cell preference | Reticulocytes |
Reticulocytes |
Reticulocytes |
Older RBCs |
| Fever cycle | 48 hours |
48 hours |
48 hours |
72 hours |
| Historic distribution in US patients 1,2 | 48.6% |
22.1% |
3.5% |
2.5% |
Origin of Infected Cases
- According to the World Malaria Report 2005, there are 350 to 500 million malaria cases worldwide.3 Nearly 60% of these cases (and 80% of the world's malaria deaths) occur in Africa, 38% in Asia, and 3% in the Americas. For falciparum malaria specifically, the respective distribution is 74%, 25%, and 1%.
- In the United States, there are
over 1500 cases of malaria, nearly all of which
are imported by
travelers or immigrants: 67% from Africa, 13% from Asia,2
and 12% from the Americas.1
Of people who
died from malaria in the United
States4 from 1959 through 1987:
- 77% took no antimalarials; (A later study, reported in 2003, still shows that only 40% of US travelers who died from malaria took prophylaxis.5)
- 13% had taken non-efficacious medications;
- 46% waited 4 to 6 days and 24% waited longer than 7 days prior to seeking medical attention; and
- 40% were not diagnosed with malaria at initial physician encounter. (The most common initial diagnosis is influenza.)
Clinical Features: Malarial disease is typified by paroxysmal fevers and general malaise. This, along with a history of travel to or residence in an endemic area, is enough to suspect the diagnosis. In sick patients without other causes for fever, this alone may in some instances be enough to begin treatment. Splenomegaly is common. Hemolysis and anemia may occur, particularly with falciparum infections. Progression to cerebral involvement, multiple organ failure, and death may occur. Altered LOC and other neurological findings suggest cerebral malaria. (Case fatality rates are as high as 30% [up to 50% in pregnant patients].)6,7
Hemolysis, hemoglobinuria, and multi-organ failure are also characteristic of severe falciparum infection. Incubation period (falciparum) is from 10 days to weeks or months, with periodic recurrences.
Other Common Complications
- Severe anemia in acute or chronic cases
- Renal failure manifested by decreased urine output, decreased glomerular filtration rate (GFR), and blackwater fever due to hemoglobinuria and sludging
- Pulmonary edema (non-cardiogenic)—bad prognosis
- Hypoglycemia—due to parasite metabolic demands
- Hypersplenism—rupture
- Seizures in 40% of cerebral malaria cases8
A malaria diagnosis can be suspected from clinical features and travel history alone; the presence of parasites on blood smears confirms the diagnosis. In heavy parasitemia, parasites may be seen on ordinary Wright’s stain done for differential counts, but a thorough search using thick and thin smears with Giemsa stain should be done if initial smear is negative. Mortality is increased if > 100 000 RBC/mm3 (6% of RBCs) are infected.9,10 An elevated serum lactic acid level is the best single lab test to predict mortality or severe morbidity. Various forms of serological testing are also available.
Management: For guidance on treatment of malaria, practitioners are highly recommended to contact the CDC at the telephone numbers or Website:
CDC Malaria Hotline: 770-488-7788, M-F 8:00 AM - 4:30 PM EST
After Hours/Weekends: 770-488-7100; ask for the malaria person on call
CDC Website: www.cdc.gov
Indications for Hospitalization
- Parasitemias more than or equal to 1% to 2% of RBCs infected
- Pregnant women, infants, elderly, immunocompromised (who are at increased risk)
- Cerebral involvement or organ failure
General Care
- Correct hypovolemia and acid/base balance. Do not fluid overload.
- Dialyze promptly if the patient has inadequate renal function. (Mortality is reduced from 75% to 26% in one series.)11
- Maintain blood glucose levels. D10 ½ NS is often required.
- Correct anemia and O2 transport problems early. Consider exchange transfusion for extreme hemolysis/anemia and high parasitemia.
- Monitor parasite density every 12 hours.
- Cardiac monitor.
- Institute therapy immediately.
For Cerebral Malaria, Hemolytic States, and Organ Failure
Initial Treatment: Parenteral Antimalarials
-
Quinidine gluconate 10 mg/kg IV (max 600 mg) over 1 to 2 hours as initial loading dose. This is ordinarily the most commonly available antimalarial in the United States, but since the development of newer antiarrhythmics, quinidine may not be as widely available as in the past. Follow with infusion of quinidine gluconate 0.02 mg/kg/min for 72 hours. Watch for hypotension and for prolongation of QRS by 50% or QT interval >0.6 sec. If this occurs, stop or slow infusion until ECG changes resolve.
Alternative IV Regimens:
- In developing countries, use quinine dihydrochloride = 20 mg/kg in 10 mL/kg of D5W over 4 hours then 10 mg/kg given over 4 hours. Repeat this dose every 8 hours for 72 hours (max 1800 mg/day). Use same precautions as in quinidine treatment, or
- (Non-US) Artesunate 4 mg/kg/day IV, IM, PR.
Continued antimalarial treatment. Once patient is able to take medications PO, parenteral medication can be discontinued. Substitute quinine sulfate 650 mg (as the salt), (PEDS: 10 mg/kg) PO twice daily for total treatment of 3 to 7 days.
Oral substitutes for parenteral antimalarials: If parenteral treatment is not possible, or the patient’s condition permits, the following can be given PO or NG:
- Atovaquone/proguanil (Malarone) 1000 mg/400 mg 4 times daily for 3 days. (PEDS: 11 to 20 kg 250/100; 21 to 30 kg 500/200; 31 to 40 kg 750/300, all 4 times daily) Or,
- Artenusate 4 mg/kg/day PO for 3 days + mefloquine 750 mg PO once then mefloquine 500 mg PO in 12 hours. PEDS: Mefloquine: <45kg = 15 mg/kg then 10 mg/kg in 12 hours.
To any of the antimalarial regimens, add:
Tetracycline 250 mg twice daily or doxycycline 100 mg twice daily or clindamycin 900 mg twice daily for 7 days. PEDS: Tetracyclines are not recommended in patients under age 8. Clindamycin dose: 10 mg/kg loading dose, then 6 mg/kg twice daily.
Treatment of Less Serious Cases of Malaria
Treatment is highly dependent on species of plasmodium and likelihood of chloroquine resistance. The practitioner is recommended to consult the CDC for the latest information on resistance patterns and treatment recommendations.
For up-to-date information and advice on treatment of malaria and prevention of malaria in travelers, see information on contacting the CDC.
Dengue and Hemorrhagic Fevers
Dengue, also known as breakbone fever is a self-limiting, mosquito-borne, viral infection characterized by fever, severe retro-bulbar headache, myalgia, arthralgia, and a late-coming morbilliform rash. Bradycardia, thrombocytopenia, and neutropenia are occasionally seen as well.
Dengue hemorrhagic syndrome also exists. Following initial infection, the patient is immune from future infection by the infecting dengue serotype. Unfortunately, should a different serotype subsequently infect the individual (there are 4 known serotypes), a severe syndrome involving disorders in capillary permeability, coagulation, and hemostasis, accompanied by shock, develops. In these cases, a typical dengue fever presentation is followed by a second phase of ascites, edema, pleural effusion, bleeding diatheses, and shock.
Treatment of both dengue fever and dengue hemorrhagic syndrome is to administer supportive care employing IV fluids, acetaminophen, oxygen, and blood or blood component transfusions as indicated.
Several other hemorrhagic fevers, of varying severity, are clinically similar to dengue hemorrhagic syndrome. Some are highly contagious and responsible for significant nosocomial transmission to both other patients and to healthcare workers. Others are spread by mosquitoes, rodent urine, and other means. (Human-to-human transmission is uncommon.) These include Yellow Fever, Lassa Fever, Ebola, Marburg, Rift Valley Fever, Crimean-Congo, and various South American hemorrhagic fevers. Treatment options are limited for all these, primarily to supportive care; however, containment is essential, and the CDC should be contacted immediately upon suspicion of any of these conditions. Contact isolation is critical.
An effective vaccine is available for yellow fever, and vaccination is wise for those traveling to endemic regions. Many governments require vaccination for travelers entering their countries from endemic areas, including those whose only activity in an endemic country was to change planes.
Spotted Fevers
Rocky Mountain Spotted Fever, the most well known of the spotted fevers, is a potentially fatal tick-borne rickettsial disease. It is found throughout the Americas, and is known by various geographically distinct names such as fiebre manchada, fiebre petequial, fiebre maculosa brasiliensis, and Sao Paulo typhus. Clinically, it has a fairly abrupt onset with fever, myalgias, and a skin rash due to a vasculitis induced by the organism’s preference for endothelial cells. Rarely, this rash may progress to frank necrosis. GI symptoms may also be prominent.
Diagnosis is primarily clinical. Serological tests are often not helpful early in the course, and blood counts are usually normal. Culture, PCR (polymerase chain reaction), and other laboratory methods of diagnosis are largely limited to research settings.
Treatment is supportive, with only two antimicrobial agents (chloramphenicol and tetracycline) demonstrating effectiveness. Drug therapy should continue at least 5 days or until patient has been afebrile for 72 hours.
Other spotted fevers include Mediterranean Spotted Fever, Japanese Spotted Fever, Flinders Island Spotted Fever, African Tick Bite Fever, and Rickettsialpox. All are rickettsial infections with presentations similar to, though generally less severe than, Rocky Mountain Spotted Fever. Many are self-limiting, and those that are not are quite responsive to tetracyclines.
Typhoid
Typhoid is characterized by fever, sustained bacteremia, and invasion of the phagocytes of the GI system, spleen, and lymph nodes. It is caused by Salmonella typhi acquired through contaminated food and water. Disease manifestations are believed to be due to contributions from the bacterial endotoxin, host immunologic reactions, and metabolic and nutritional status of the patient.
The clinical picture is variable, and may have a 50% mortality rate for severe inpatient cases, although 1.5% to 15% is more typical.9,12 Following ingestion of the organism, most patients experience transient diarrhea followed by 3- to 60-day incubation. Flu-like symptoms develop along with the fever and bacteremia. After 3 weeks, the fever abates in most patients, but intestinal perforation and hemorrhage may occur at this time (at the site of affected mucosal Peyer’s Patches). Less commonly, DIC, pulmonary, cardiovascular, neuropsychiatric, genitourinary, or hepatobilliary signs may be seen. Relapses occur in patients with metastatic foci. Three percent of patients become chronic (asymptomatic) carriers.10
Diagnosis is largely clinical, and may be confirmed by serology, PCR, or culture.
The mainstay of therapy for typhoid is supportive (fluid, electrolytes, nutritional). Treatment with antibiotics early in the course of the disease has been shown to shorten the course and reduce rate of complications and fatality. Some antibiotics, however, may increase the relapse rate. Multidrug resistant typhoid exists, in which case the quinolones are the agent of choice, even in children.
Paratyphoid is similar to typhoid but generally less severe. The treatment is the same.
Antibiotics in Typhoid/Paratyphoid
| Agent | Route | Dose (mg/kg/day) |
Frequencey |
| Amoxicillin | PO |
75-100 |
3 X daily |
| Ampicillin | PO/IV/IM |
100-150 |
3 X daily |
| Bactrim | PO/IV |
6.5-10 |
2 X daily |
| Cefoperazone | IV |
50-100 |
2 X daily |
| Cefotaxime | IV |
100-150 |
3 X daily/ 4 X daily |
| Ceftriaxone | IV/IM |
50-80 |
2 X daily |
| Chloramphenicol | PO/IV |
50 |
4 X daily |
| Ciprofloxacin | PO/IV |
20-30 |
2 X daily |
| Ofloxacin | PO/IV |
10 |
2 x daily |
| Duration of treatment is 10 days after defervescence, except for cephalosporins, for which the total course is 10 days, and quinolones, for which the total course is 14 days. | |||
Typhus
Typhus is another group of rickettsial infections related to typhoid. Louse-borne typhus is acquired by inadvertently scratching the infected feces of the human body louse into the skin (responding to the pruritus of the louse bite). Following an incubation of 1 ½ weeks, fever, myalgia, headache, and prostration develop and may be accompanied by acute cognitive changes. Pneumonia, myocarditis, meningitis, and encephalitis may later develop. If untreated, mortality is high.
Diagnosis is clinical, particularly in the setting of an epidemic. Serology (Weil-Felix test) and PCR may be helpful if available.
As with typhoid, treatment is largely supportive. In addition, tetracycline (500 mg PO/IV 4 times daily for 7 days), doxycycline (200 mg PO once per day for 7 days), or chloramphenicol (500 mg PO/IV 4 times daily for 7 days) is beneficial. Doxycycline 200 mg given once serves as effective post-exposure prophylaxis.
Scrub typhus (also known as Tsutsugamushi fever) and African tick typhus are similar in their clinical manifestations, though generally less severe, and are acquired from mites and ticks, respectively, rather than lice. The treatment is the same.
Relapsing Fevers
These conditions are caused by Borrelia infection, a relative of the Lyme disease organism. There are louse-borne (epidemic) and tick-borne (endemic) forms. Following inoculation of the spirochete by the arthropod bite, a 4 to 8 day incubation period occurs. Then, a high fever abruptly appears, accompanied by cephalgia, confusion, meningeal signs, myalgia, arthralgia, and GI and respiratory symptoms. Later, nephritis, myocarditis, encephalitis, and other manifestations may appear. Fatality rates in epidemic relapsing fever may reach 70%, while in endemic forms, the rate is below 10%.13 Diagnosis is often by identification of the large spirochete on a blood smear prepared to look for malaria. Serology is unreliable.
Fortunately, treatment is quite effective. A single dose of antibiotic is curative in over 80% of cases; a longer (10-day) course bumps this up to nearly 100%.9,13 Tetracyclines, penicillins, macrolides, and quinolones are all effective.
One complication of treatment worth noting is the Jarisch-Herxheimer reaction, which may be fatal. A couple of hours after the first antibiotic, rigors, anxiety, and restlessness appears and may progress to compensated—then decompensated—shock. Close monitoring with fluid resuscitation as necessary is warranted on initiation of treatment. Opioid antagonist treatment may help; steroids do not.
Miscellaneous Fevers
Brucellosis
Acquired by ingestion of unpasteurized dairy products, or
occasionally through
body fluids, bacterial infection presents with
recurrent bouts of fever. Occasionally, focal musculoskeletal symptoms
may also be present. Mild
meningoencephalitis, orchitis, cough, leukopenia, and thrombocytopenia
may be
found. Non-caseating granulomas may be found, and are difficult to
differentiate
from tuberculosis. Diagnosis may be challenging. Bone marrow culture is
more
sensitive than multiple blood cultures. Serology is of variable value,
and may
have a high false negative rate.
Treatment is based on whether the infection is acute, relapsing, or chronic; whether or not joints and bones are focally involved; and whether or not tuberculosis has been excluded. Acute, nonfocal disease requires a minimum of 6 weeks therapy; focal or chronic should be treated for 3 months. Monotherapy leads to relapse in one-third of cases.13 Regimens include doxycycline 100 mg twice daily for 6 to 12 weeks plus streptomycin IM 1 g four times daily for 2 to 3 weeks, substituting gentamicin (5 mg/kg/day for 1 week) for the streptomycin, or substituting Bactrim DS twice daily in place of the doxycylcine (eg, pregnancy). If tuberculosis has not been excluded, it should be treated simultaneously. PEDS: Some evidence indicates that children under 12 can be adequately treated for 3 weeks rather than for 6 weeks as in adults.
Leptospirosis
Leptospira
is a common bacteria in animals. Humans acquire leptospirosis
infection through exposure of wounds, mucous membranes, and
conjunctivae to
contaminated water. Following 1 to 2 week incubation, a transient
bacteremia occurs, after which the organisms are deposited in various
tissues. A high fever
accompanied by myalgia, weakness, diarrhea, and vomiting is not
uncommon
during this time. Subsequently, an aseptic meningitis, a severe icteric
illness
(including hepatorenal failure and hemorrhagic symptoms), or a
pulmonary
syndrome associated with acute renal failure and adult respiratory
distress
syndrome (ARDS) may also develop. The pathology seems to be related to
the lysis
of the organisms.
As with many conditions in this chapter, diagnosis is largely clinical. Blood and urine cultures may be helpful, as may serological or PCR testing.
Supportive therapy is the most important aspect of treatment in these seriously ill patients. Attention to fluid and electrolytes in the context of renal failure is key, and transfusion as indicated for the blood loss. Dialysis may be required. Doxycycline may shorten the course, but does not prevent kidney failure, and a mild Jarisch-Herxheimer reaction (discussed previously under relapsing fevers) may occur.
Babesia
A tick-borne infection by a malaria-like organism, babesiosis
is more common in
rodents or cattle than
humans. It is endemic
in the temperate United States and
Europe, but also in the subtropics. Clinically, it ranges from
asymptomatic to
high fever with severe
hemolytic anemia, jaundice, renal failure, and death. Severity depends
on species of
Babesia,
but also the immune status of the host.
Diagnosis is via blood smear, like malaria, where the organisms form a Maltese cross appearance. Serology or PCR are also available if the infection is suspected.
Treatment consists of quinine (650 mg PO every 8 hours) plus clindamycin (600 mg PO every 8 hours) for 10 days, or atovaquone (750 mg PO twice daily) plus azithromycin (500 mg PO day 1, 250 mg PO days 2 through 5) for 5 days.
Bartonellosis
Bartonellosis is a bacterial infection spread by sand flies,
and there are two forms. The more malignant form, Oroya fever, presents
with high fever and the rapid
development of macrocytic anemia. An apparent clinical improvement may
be
followed by sepsis
from other organisms, complicated by thrombocytopenic
purpura and a 50% mortality
rate.7 The more
benign form, verruga peruana, presents as nodular hemangiomas
developing over the course of a couple of
months. Ulceration and hemorrhage is common; coinfection with other
organisms is rarely fatal. The distribution of this infection is
limited
to the Andes, between 800 and 3000 meters elevation between the
latitudes of 2º
N and 13º S.
Diagnosis is clinical, coupled with demonstration of the organism on blood film or culture.
Treatment using penicillin, streptomycin, chloramphenicol, or tetracycline is successful.
Q Fever
Caused by a rickettsia-like organism, Q
fever
is transmitted by milk products
from domestic goats and cattle, and occasionally through exposure to
feces or
tick bites. Though usually mild, lung, liver, and heart may be
affected. Cardiac
involvement occurs in 10% of cases,6 and may
include destructive valve lesions, which
become apparent many months after infection. Diagnosis is serological;
treatment is similar to
typhus.
Trench Fever
A usually mild
febrile rickettsial infection transmitted by lice. Diagnosis and
treatment is the same as Q fever.
References
- Thwing J, Skarbinksi J, Newman RD, et al. Malaria surveillance—United States, 2005. MMWR Surveillance Summaries. 2007 Jun 8;56(SS06):23-38. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/ss5606a2.htm. Accessed April 8, 2008.
- Freedman DO, Weld LH, Kozarsky PE, et al. Spectrum of disease and relation to place of exposure among ill returned travelers. N Engl J Med. 2006;354:119-130.
- World Health Organization Roll Back Malaria Department and United Children’s Fund. World Malaria Report 2005. Available at http://rbm.who.int/wmr2005/html/1-2.htm. Accessed May 20, 2008.
- Greenberg AE, Lobel HO. Mortality from Plasmodium falciparum malaria in travelers from the United States, 1959 to 1987. Ann Intern Med. 1990;113:326-327.
- Stoppacher R, Adams SP. Malaria deaths in the United States: case report and review of deaths, 1979-1998. J Forensic Sci. 2003;48:404-408.
- Cook GC, Zumla A, editors. Manson’s tropical diseases, 21st ed. Philadelphia, PA: WB Saunders, 2003.
- Strickland GT, editor. Hunter’s tropical medicine and emerging infectious diseases, 8th ed. Philadelphia, PA: WB Saunders, 2000.
- Idro R, Ndiritu M, Ogutu B, et al. Burden, features, and outcome of neurological involvement in acute falciparum malaria in Kenyan children. JAMA. 2007; 297:2232-2240.
- Guerrant RL, Walker DH, and Weller PF, editors. Tropical infectious diseases: principles, pathogens, and practice. Philadelphia, PA: Churchill-Livingstone, 1999.
- Warrell DA, Molyneux ME, Beasles PF. Severe and complicated malaria. Trans R Soc Trop Med Hyg. 1990;84:1.
- Trang TT, Phu NH, Vinh H, et al. Acute renal failure in patients with severe falciparum malaria. Clin Infect Dis. 1992;15:874-880.
- Hohmann EL. Pathogenesis of typhoid fever. Available at www.uptodate.com. Accessed March 25, 2008.
- Gill GV, Beeching NJ. Lecture notes in tropical medicine, 5th ed. Malden, MA: Blackwell Science, 2004.