Getting Sick in the Tropics (Tropical IDs) Part 2: Typhoid Fever & Malaria Dr.

Rosario
I. OUTLINE: Part 1: Overview A. Tropical infectious diseases B. 10 leading causes of morbidity Dengue A. Dengue virus B. Transmission of dengue virus by aedes aegypti C. Dengue infections D. Pathophysiology E. Course of illness F. Old WHO dengue classification G. Dengue case classification and levels of severity H. Diagnosis I. Tourniquet test J. Step-wise approach to management of dengue K. Group A L. Home care for dengue M. Admission criteria N. Group B O. Group C P. Effects of supportive treatments for DHF or DSS in children Q. Group C: emergency treatment R. Summary of blood transfusion treatment S. Discharge criteria T. Prognosis U. Prevention Part 2: Typhoid fever A. Etiologic agents B. Enteric fever C. Complications and consequences D. Laboratory tests E. Antibiotic therapy F. Case course G. Prevention IV. Malaria A. Etiologic agents B. Transmission cycle C. Laboratory tests D. Clinical features E. Major signs of severe malaria F. Other signs of severe malaria G. Drugs for susceptible plasmodium H. Drugs for MDR I. Drugs for severe or complicated P. falciparum malaria J. Primaquine K. Other issues III. Part 3: Leptospirosis

Lets imagine it happened

II.

o S/Sx result from cytokine secretion in response to bacterial products after critical no. of organisms have replicated S. paratyphi A causes milder disease than S. typhi Occurrence of multidrug resistant (MDR) strains of S. typhi o Contain plasmids encoding resistance to chloramphenicol, ampicillin, trimethoprim o Abx long used to treat typhoid fever ENTERIC (TYPHOID) FEVER: MANIFESTATIONS Systemic disease characterized by fever and abdominal pain and caused by dissemination of S. typhi or S. paratyphi. Incubation period: 3-21 days (ave. 10-14 days) Most prominent sx: prolonged fever (38.8-40.5oC) if untreated Early findings: rash, hepatosplenomegaly, epistaxis, relative bradycardia at peak of high fever Rose spots faint salmon colored, blanching, maculopapular rash located primarily on the trunk and chest; evident at end of 1st week; resolves after 2-5 days

COMPLICATIONS AND CONSEQUENCES

[Harrisons] Development of severe disease depends on host factors (immunosuppression, antacid therapy, previous exposure, vaccination), strain virulence and inoculum, and choice of antibiotic therapy.

TYPHOID FEVER
Case # 2: 25 year old, female, government employee Intermittent fever and chills for seven days, relieved temporarily by paracetamol Headache, myalgia, body malaise and vague abdominal pain History of diarrhea x 1 day She denies travel to remote area o Unremarkable PE except for T= 38.6 C
o Fever with normal heart rate relative bradycardia: seen in patients with typhoid fever and legionella infection) [2013B]

Intestinal hemorrhage o Severe GI bleeding Intestinal perforation Peritonitis Kidney failure Orchitis Chronic carrier states Myocarditis
Neurologic manifestations o Encephalitis (Psychosis) o Meningitis, Guillain-Barr syndrome, neuritis, and neuropsychiatric symptoms (described as "muttering delirium" or "coma vigil"), with picking at bedclothes or imaginary objects. [Harrisons]

LABORATORY TESTS
Case 2 Lab Results: CBC: Hgb= 14.3 Hct= 0.47 RBC = 3.85 WBC = 6.5 N=70 L=26 E=1 M=3 Platelet count= 190,000 Urinalysis (-) Typhidot: IgM (-); IgG (+) Question: What laboratory examination would be the most helpful test before starting any antibiotic? A. Complete blood count B. Urinalysis C. Immunochromatographic test (Typhi Dot) D. Blood culture and sensitivity
[2013B] Immunochromatographic Test (Typhi Dot) o Antibody test; tells previous exposure; it may not truly tell if there is a disease Blood culture and sensitivity o Isolates organisms; best tool

Case # 2: Issues
Absence of focal findings o Non-specific signs and symptoms o Clues in the clinical data: historical/ suggestive physical findings Possible etiologic agent o Standard diagnostic procedure Empiric therapy o Drug of choice Resistance patterns
ETIOLOGIC AGENT [Harrisons] SALMONELLA S. typhi or S. paratyphi serotypes A, B, C Gram-negative, non-spore forming, facultative anaerobic bacilli Growth restricted to human hosts Mode of transmission: ingestion of organisms in contaminated food or water d/t fecal contamination by ill or asymptomatic chronic carriers. Pathogenesis: o Penetrates and targets small intestine; phagocytosed by macrophages o Spread to other organs via lymphatics and colonize RES tissues

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RATIONALE FOR THE DIAGNOSTIC TEST

To determine the etiologic agent o Better care o Cost efficient In suspected cases of typhoid fever o Isolation via cultures remains the gold standard st nd o Blood in the 1 and 2 week rd o Stool in the 3 week rd o Urine culture may become (+) on the 3 week

ANTIBIOTIC THERAPY FOR TYPHOID FEVER

Question: Which of the following antibiotics would you give? A. Chloramphenicol B. Amoxicillin C. Cotrimoxazole D. Ciprofloxacin
[2013B] Antibiotic Therapy for Typhoid fever Optimal Therapy Antibiotic Daily Days dose mg/ Kg

Figure 9. Trends in Antimicrobial Resistance among Salmonella Typhi Isolates 1988-2009 ARSP

Susceptib ilty

Alternative effective drugs Antibiotic Daily days dose mg/kg

Figure 10. Trends in Antimicrobial Resistance among Non-typhoidal Salmonellae 1988-2009 ARSP

CASE COURSE
Chloramphenicol Amoxicillin TMP-SMX 50-75 75-100 14-21 14 14

Fluoroquinolone e.g. ofloxacin, ciprofloxacin

15

5-7

Case # 2 Course: The patient was started on oral chloramphenicol However, he continued to have fever nd 2 HD: abdominal pain increased in intensity hematochezia Blood culture is positive after 48 hours Question: How would you modify your antibiotic therapy? A. Shift initial antibiotic to a parenteral form B. Change the initial antibiotic to an IV fluoroquinolone C. Add an IV third generation cephalosporin (e.g. Ceftriaxone) D. Continue initial antibiotic therapy and wait for the susceptibility results
[2013B] Continue initial antibiotic therapy and wait for the susceptibility result o Because chloramphenicol is not good when given IV; youre already dealing with the complicated type of typhoid fever (note hematochezia) + resistant typhoid = change Abx

Fully susceptible Multi-drug resistant

Fluoroquinolone Or Cefixime

15 15-20

5-7 7-14

Azithromycin Cefixime

8-10 15-20

7 7-14

Quinolone resistant

Azithromycin

8-10

Cefixime

20

7-14

Three-day courses are also effective, particularly in epidemic containment The treatment for quinolone resistant typhoid fever has not been determined. Azithromycin, the third generation cephalosporins, 10-14 day course of high-dose fluoroquinolones, is effective. Combination of these is also being evaluated. 3 First-line Agents in Philippines: 1. Chloramphenicol 2. Amoxicillin/ Ampicillin 3. Co-trimoxazole [Harrisons] Prompt administration of appropriated antibiotic therapy prevents severe complications and results in a case fatality rate of <1% Drug susceptible typhoid fever o Fluoroquinolones most effective class of agents Patients with nalidixic acid-susceptible strains o Ceftriaxone, azithromycin, or high dose ciprofloxacin Most preferred

Blood CS result (related to case course): Salmonella sp. o Sensitive to ciprofloxacin, ceftriaxone, amikacin o Resistant to chloramphenicol, ampicillin The antibiotic was shifted to intravenous ciprofloxacin 400 mg every 12 hours Abdomen was regularly examined; no signs of peritonitis were observed on subsequent days o No episode of hematochezia was reported o Urine output was adequate After 3 days of IV ciprofloxacin, temperature levels started to th go down; lysis of fever was noted on the 5 day of the antibiotic

PREVENTION
Proper hygiene Avoid possibly contaminated food and water Vaccines for high risk groups
[Harrisons] Two Typhoid vaccines are commercially available: o Ty21a, an oral live attenuated S. typhi vaccine (given on days 1, 3, 5, and 7, with a booster every 5 years)

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o Vi CPS, a parenteral vaccine consisting of purified Vi polysaccharide from the bacterial capsule (given in 1 dose, with a booster every 2 years)

MALARIA TRANSMISSION CYCLE

[Harrisons] Malaria Protozoan disease; transmitted by the bite of an infected female Anopheles mosquitoes Principal determinants of the epidemiology of malaria: number (density), human-biting habits, longevity of anopheline mosquito vectors Transmission of malaria is directly proportional to the density of vector

MALARIA
Case # 3: A 35 year old male who had a recent travel to Palawan 1 week after arriving in manila, sudden onset of fever, chills, severe headache, and body malaise Consulted 2 days later: CBC, malarial smear and urinalysis showed normal results Given Ciprofloxacin 750 mg BID x 5 days with no lysis of fever Admitted because of subsequent development of oliguria and ictericia

Case # 3: Issues
Disease severity/ comorbid conditions or factors o Ictericia o Oliguria Etiologic agent involved o Drug of choice o Drug resistance

Figure 12. Plasmodium sporozoites 1st vector (Plasmodium sp.) initial human host liver infection blood infection 2nd vector next human host [2013B]

ETIOLOGIC AGENTS PLASMODIUM FALCIPARUM

Only species associated with severe or complicated malaria o Almost all deaths caused by this specie [Harrisons] Problem with therapy: Multidrug resistance o Philippines: increasing chloroquine and sulfadoxinepyrimethamine resistance DOH surveillance rate: 35- 65% Highest in Palawan
Clue: in a smear, you should see multiple affected RBC presenting with rings [2013B]

LABORATORY TESTS
Question: Which diagnostic test would be most helpful? A. Complete blood count B. Renal and liver function tests C. Malarial smear D. Blood C/S E. Microcapsular agglutination test
[Harrisons] Remember: The diagnosis of malaria rests on the demonstration of asexual forms of the parasite in stained peripheral blood smears. LABORATORY FINDINGS Normochromic, normocytic anemia is usual Leukocyte count: generally normal (may be raised in severe infections) Slight monocytosis, lymphopenia, eosinopenia w/ reactive lymphocytosis and eosinophilia weeks after acute infection ESR, plasma viscosity, C-reactive protein and other acute-phase protein: High Platelet count is usually reduced to 105/L

Figure 11. Malaria blood smear showing ring forms

OTHER PLASMODIUM SPECIES

Plasmodium vivax and ovale o Both can cause relapse A proportion of the intrahepatic forms (hypnozoites) remain
dormant for a period ranging from 3 weeks to a year or longer before reproduction begins Hypnozoites are the cause of relapses [Harrisons]

Case # 3 Lab results: CBC: Hb=9.0, Hct=28.7, RBC=2.95 WBC=14.0 (N=81, L=17 M=2), platelet count=95,00 LFTs: ALT = 120 Iu/l, AST = 96 Iu/l, AP = 54 Iu/l, B2 =15mol/l, TB = 65mol/l, Crea = 200mol/l. MAT = positive at 1:100 Blood CS: NG after 24 hours
[2013B] In most malaria cases, patients would present with elevated white blood cells, but some may present with thrombocytopenia Liver function test results in a patient w/ Malaria: o Slightly elevated ALT o Slightly elevated AST o Normal alkaline phosphatase o Creatinine is elevated = 200 o MAT = 1: 100 Philippine cut-off : 1:1600

Plasmodium malariae o Causes nephropathy Plasmodium knowlesi o Similar to plasmodium malaria but behaves like P.falciparum
infection

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CLINICAL FEATURES OF MALARIA [Harrisons] Nonspecific first symptoms: lack of sense of well-being, headache, fatigue, abdominal discomfort, and muscle aches followed by fever Headache present but no neck stiffness or photophobia resembling meningitis. Myalgia may be prominent but not usually as severe as in dengue; and muscles are not tender as in leptospirosis or typhus. When fever spikes, chills and rigors occur at regular intervals suggest P. vivax or P. ovale infection. Irregular fever Falciparum malaria Few abnormal physical findings other than fever, malaise, mild anemia, palpable spleen (some cases). Slight enlargement of liver particularly among children. Mild jaundice is common among adults and develops in patients with uncomplicated falciparum malaria; usually resolves over 1-3 weeks. Malaria is not associated with rashes.

DRUGS FOR SUSCEPTIBLE PLASMODIUM SP.

Question: Which of the following anti-microbials would you give? A. Chloroquine + Sulfadoxine/Pyrimethamine B. Quinine + Doxycycline C. Artemether + Lumefantrine D. Primaquine Uncomplicated malaria o Susceptible P. Falciparum Chloroquine can cause tinnitus [2013B] Sulfadoxine/pyrimethamine o Other susceptible Plasmodium sp. Chloroquine
One criteria that you have to consider in choosing drugs is resistance of species In the Philippines, more than 60% is resistant especially in Palawan

MAJOR SIGNS OF SEVERE MALARIA

Unarousable coma/ cerebral malaria Failure to localize or respond appropriately to noxious stimuli; coma should persist for >30 min after generalized convulsion Hematocrit <15% or haemoglobin <5g/dl with parasitemia level >10,000 per L

DRUGS FOR MULTI-DRUG RESISTANCE PLASMODIUM FALCIPARUM MALARIA

Artemether-lumefantrine (Co-Artem) 1.5/9 mg/kg BID with food for 3 days (or artesunate 4mg/kg qd) PLUS Mefloquine 15-25 mg base/kg for 3 days

Severe normocytic, normochromic anemia Renal failure

Pulmonary edema/ adult respiratory distress syndrome Hypoglycemia

Urine output <400 mL/24 h in adults or 12 mL/kg per 24 hr in children; no improvement with rehydration; serum creatinine >265 mol/L 93 mg/dl) Noncardiogenic pulmonary edema often aggravated by overhydration
[Harissons 18 ed]
th

DRUGS FOR SEVERE OR COMPLICATED P. FALCIPARUM MALARIA

Drug/s of choice: IV quinine (or quinidine) + Doxycycline or clindamycin Alternative: Artemisinin derivatives

Glucose <2.2 mmol/L (<40mg/dl)

PRIMAQUINE
For radical cure Used as gametocidal drug for P. Falciparum malaria Used as a hypnozoiticidal drug for P. Vivax or P. Ovale infection to prevent relapse
[2013B] Contraindications: Patients with G6PD deficiency hemolysis Not used for active disease

Hypotension/shock

Systolic blood pressure <50 mmHg in children 1-5 years or < 80 mmHg in adults ; core skin temperature difference >10C Significant bleeding and hemorrhage from the gums, nose, GIT, and/ or evidence of disseminated intravascular coagulation More than 2 generalized seizures in 24 hours Arterial pH< 7.25 or plasma bicarbonate< 15 mmol/ L, venous lactate > 6 mmol/ L Macroscopic black, brown, red urine, not associated with effects of oxidant drugs and red blood cell enzyme defects (such as G6PD deficiency)

Bleeding/ Disseminated intravascular coagulation Convulsions Acidemia/ acidosis Hemoglobinuria

OTHER ISSUES
1. Management of Complications 2. Adverse events related to drug interventions and interactions 3. Prevention

Management of Complications
[2013B] Regarding hypoglycemia, quinine can induce insulin release which can aggravate hypoglycaemia Pulmonary edema: unknown reason why patients develop this, so ventilatory support should be given Acidosis: give bicarbonate Renal failure: require dialysis

OTHER SIGNS OF SEVERE MALARIA

Impaired consciousness Unable to sit or stand without support
[Harrisons 18 ed]
th

Extreme weakness

Prostration; unable to sit unaided

[Harrisons 18 ed]

th

Hyperparasitemia Jaundice Hyperpyrexia

Parasitemia >5% in nonimmune patients Serum bilirubin level >50 mmol/ L (>3 mg/dl) Rectal Temperature >40C

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Prevention
Chemoprophylaxis Use mosquito nets. It is more effective if the mosquito net is treated with
insecticide Use long sleeves and pants Use repellants and screens on doors and windows Clear hanging branches of trees along the streams Have your blood examined if you have the signs and symptoms of malaria Follow the advice of health workers on how to take anti- malaria drugs. Primary area where Malaria is endemic- PALAWAN Avoidance of exposure to mosquitoes at their peak feeding times (usually dusk to dawn) as well as the use of insect repellents containing 1035% DEET

QUIZ: 1. 2. 3.

What Plasmodium species causes relapse in malaria? Which among the dengue serotype causes the more severe disease? What is the drug of choice for the treatment of typhoid fever in the Philippines?

Answers: (1) P. vivax & P.ovale; (2) Serotype 2; (3) Chloramphenicol

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