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Management of malaria and non-malaria febrile illnesses ValĂŠrie D'Acremont Swiss Tropical & Public Health Institute Global Malaria Programme, WHO

Seattle, 20 Oct 2011


Background Prescription of antimicrobials for children underfive in Dar es Salaam, Tanzania Antimalarials

AND

Antibiotics 15%

57%

79% 75%

Routine microscopy (or no malaria tests)

Rapid Diagnostic Tests 2


Objective

To determine the etiology of fever episodes in children living in urban and rural Tanzania

Dar Es Salam 3 mio d’habitants

Ifakara, 50.000 hab.

3


Methodology

• Prospective study including children attending two outpatient clinics (one urban and one rural) in Tanzania

• Inclusion criteria: - aged 2 months - 10 yrs - temperature > 38°C - no antimicrobials for > 1week

• Full clinical assessment • Investigations based on pre-defined algorithms: FBC; ALT; creat.; RDT for malaria, typhoid, strepto A, adeno/rotavirus; BS malaria and borrelia; urine dipstick; amoeba in stool; blood/urine/stool cultures; chest X-ray

4


Methodology Example of a pre-defined algorithm: Diarrhea (>3 stools/day): POS

Amoebic GASTRO-ENTERITIS

1) Investigation for diarrhea

Stool examination for amoeba NEG

POS

POS Rapid Test for Typhoid NEG

Viral GASTRO-ENTERITIS

STOP

STOP

No antibiotic

Rapid test Rota/adeno NEG

2)

Metronidazole

TYPHOID

Follow-up Day 7

Possible bacterial GASTRO-ENTERITIS

Ciprofloxacine

STOP

Ciprofloxacine

3)

Follow-up Day 7

Blood culture

5


Methodology

Real-time (RT-)PCR of naso-pharyngeal swabs for 15 virus: FLUAV, FLUBV, RSV, HMPV, HPIV 1/3, PIC (rhino, entero, coxsackie), HBoV, HCoV OC43 229E NL63 HKU1, HAdV

Real-time PCR on blood: Dengue, Chikungunya, West Nile, Rift Valley HHV6, parvovirus B19

Serologies on blood : EBV, CMV, Toxoplasma, Rickettsia, Coxiella, Leptospira

Computer-based diagnosis with levels of probability 6


Baseline characteristics

From April to December 2008:

1005 children were included (informed consent, 2 refusals) 507 in Dar es Salaam and 498 in Ifakara

median age was 18 months

49% were females

78 (8%) children were admitted in the ward

133 (13%) had WHO criteria for severe disease (4 deaths) 7


Etiologies of fever in 1005 Tanzanian children Malaria

Typhoid Meningitis

0.2%

3% 9%

Systemic infections

11% Skin infection

1% 50%

5% Urinary tract infection

Acute respiratory infection

8% Gastroenteritis

13%

Fever?

1212 diagnoses 8


Overlap of diseases 19.6% had 2 or more diagnoses of high probability

ARI 52.8% 3.6%

Malaria 6.7%

Clinical pneumonia* 14.6%

% 0.2

4%

Gastroenteritis 5.9%

*Pneumonia as defined by WHO (documented or not by chest X-ray) 9


Etiologies of Acute Respiratory Infections (ARI) Malaria

Typhoid Meningitis

0.2%

3% 9%

Systemic infections

11% Skin infection

1% 50%

5%

ARI

Urinary tract infection

8% Gastroenteritis

13%

Fever? 10


Etiologies of Acute Respiratory Infections (ARI) Radiological pneumonia Clinical pneumonia

Bronchiolitis

5% 22% 7%

ARI 65%

URTI

50%

81% Viruses 11


Etiologies of Acute Respiratory Infections (ARI) Radiological pneumonia Clinical pneumonia

Bronchiolitis

5% 22% 7%

ARI 65%

URTI

50% Influenza Coronavirus Bocavirus Adenovirus

RSV

81%

Metapneumovirus Parainfluenza 1/3

Enterovirus Rhinovirus 12


Seasonality of influenza 50%

Dar es Salaam 40%

Influenza A

30%

Influenza B

20% 10% 0%

Apr

May

Jun

Jul

Aug

50%

Ifakara

40% 30% 20% 10% 0%

Jul

Aug

Sep

Oct

Nov

13


Etiologies of gastroenteritis Malaria

Typhoid Meningitis

0.2%

3% 9%

Systemic infections

11% Skin infection

1% 50%

5%

ARI

Urinary tract infection

8% 13% Gastroenteritis Fever? 14


Etiologies of gastroenteritis

Rotavirus Adenovirus 28%

Unknown pathogen

51% 18%

4%

Salmonella Shigella

8%

Amoeba Gastroenteritis

15


Etiologies of systemic infections Malaria

Typhoid Systemic Meningitisinfections 3%

0.2%

9%

11% Skin infection

50%

5%

ARI

Urinary tract infection

8% Gastroenteritis

13%

Fever? 16


Etiologies of systemic infections

Systemic infections

11%

75%

8% Viruses

17


Etiologies of systemic infections

Coxiella Leptospira

Systemic infections Toxoplasma

Rickettsia Common bacteremia Mumps

11%

VZV

75%

Parvovirus B19

HHV6

EBV CMV

8%

Viruses

No Dengue, No Chikungunya, No West Nile, No Rift Valley 18


Summary of findings

• In Tanzanian children, half of fevers are due to acute respiratory infections (ARI)

• A quarter of ARI were due to influenza • 81% of the children were infected with one or more viruses • Malaria (9%), urinary tract infection (5%) and typhoid (3%) were much less prevalent than clinicians think

• In children: cosmopolitan >>> tropical vector-borne pathogens • Children rarely had more than one significant diseases at a time • 47% of severe patients were not admitted to the ward 19


Guidelines: IMCI and iCCM Danger signs

YES

REFER

Antimalarials and antibiotics

NONO

POS

Fever <7 days

Cough

Diarrhea

Malaria test

Fast breathing

Blood in stool

NEG Malaria ACT No drug

YES

NO

YES

Pneumonia

Cold

Dysentery

Amoxicillin

No drug

Ciprofloxacin

Salbutamol

Ear pain

NO ‘Watery’ diarrhea ORS + Zinc

Acute otitis media Amoxicillin

20


The way forward

â&#x20AC;˘

In our study, only 27% had a disease that needs antibiotics

â&#x20AC;˘

If we had applied the IMCI algorithm to these children, 25% would have received antibiotics, BUT:

Our study

15%

12%

13%

IMCI

21


The way forward in diagnostics How can we improve the IMCI clinical algorithm with available tools? 1) including the clinical predictors found in the fever study 2) adding diagnostic tests to RDT for malaria : - RDT for influenza or RSV (cough) ? - chest Xray (clinical pneumonia) ? - urine dipstick (children <2 years) ?

ALMANACH

- RDT for typhoid (children >2 years) ?

Our study

9%

18%

17%

22


The ‘fever stick’ We need a rapid and portable test that detects (malaria and) ONLY patients in need for antibiotics: BUT who are they? All patients who have no respiratory virus? All patients who have a ‘respiratory bacteria’? All patients who have a bacteria in blood (including typhoid)? NO, so what?

Biomarkers of severity… … with a clever combination of the above. 23


Implications for treatment of febrile illnesses

Based on what we are presently able to diagnose: (excluding severe and immunosuppressed children)

Amoxicillin for clinical pneumonia and acute otitis media

Oseltamivir for influenza (children <2 years, chronic condition)

Inhaled salbutamol + spacer for wheezing

ORS + Zinc for diarrhea

Ciprofloxacin for UTI, bloody diarrhea (and typhoid)

Cloxacillin for significant skin infection

Tetracyclin eye ointment + vitamine A for measles

18% 64% 24


Acknowledgements DSM City Medical Office of Health, Tanzania Judith Kahama (co-researcher) Ndeniria Swai (research assistant) Gerumana Mpawa (logistics and data entry) Ministry of health and Welfare, Tanzania Deo Mtasiwa (Chief Medical Officer) Ifakara Health Institute, Tanzania Hassan Mshinda (ex-director) Amana and St Francis hospital, Tanzania Willy Sangu and P. Kibatala (directors) Swiss Tropical and Public Health Institute Blaise Genton and Christian Lengeler Hôpitaux Universitaires de Genève Laurent Kaiser, Pascal Cherpillod, Yves Thomas, C. Tapparel

Special thanks to lab technicians who performed 28’352 microbiological tests …

Financial support from the Swiss National Science Foundation

25


dacremont2_oct202011