The prognostic value of dipstick urinalysis in children admitted to
hospital with severe malnutrition.
Nahashon Thuo1, Eric Ohuma1, Japhet Karisa1, Alison Talbert1, James A Berkley1,
2
Kathryn Maitland1,3
Affiliations:
1
Centre for Geographic Medicine Research (Coast), Kenya Medical Research Institute,
P. O. Box 230, Kilifi, Kenya
2Centre
for Clinical Vaccinology and Tropical Medicine, University of Oxford,
Headington, UK
3Imperial
College, London, UK
Keywords:
Severe malnutrition, UTI, Dipstick, Urinalysis, Prognosis
Word count:
Abstract
248
Main text
2508
Author for Correspondence:
Nahashon Thuo
Centre for Geographic Medicine Research (Coast), Kenya Medical Research Institute.
P.O. Box 230, Kilifi, Kenya
Telephone: +254 41 7522063
Fax: +254 41 7522390
Email: nthuo@kilifi.kemri-wellcome.org
Abstract
Background
Children with severe malnutrition (SM) present to hospital with an array of
complications, resulting in high mortality despite adherence to World Health
Organization guidelines. Diagnostic resources in developing countries are limited and
bedside tests would help identify high-risk children. Dipstick urinalysis is a bedside
screening test for urinary tract infections (UTIs). UTIs are common in SM and can lead
to secondary invasive bacterial sepsis. Very few studies have examined the usefulness
of dipstick screening of urine specimen in SM and none has explored its prognostic
value.
Patients and Methods
A 2 year prospective study on children admitted in Kilifi district hospital, Kenya, with SM.
Freshly voided, clean catch urine samples were tested using Multistix reagent test
strips, and positive samples sent for culture.
Results
Out of the 667 children admitted, 498 children (75%) provided urine samples; of these,
119 (24%) were positive for either leucocyte esterase (LE) or nitrites. Twenty eight
children (6% overall) had UTI confirmed by urine culture. All isolates were coliforms ;>
50% were resistant to cotrimoxazole and gentamicin. There was no difference in signs
of severity between those with positive urine dipstick and those without. Case fatality
was higher among children with a positive dipstick (29% vs. 12%). Presence of a
positive dipstick was a strong predictor of mortality (adjusted HR: 2.76)
Conclusions
A urine dipstick positive for either LE or nitrites is a useful predictor of death in children
admitted with SM and can help guide antimicrobial treatment.
Introduction
Children with severe malnutrition (SM) presenting to hospital often have an array of
complications. As a consequence, management with a single protocol is challenging
and may not be optimal for all groups. In particular, children with SM are at risk of
infection(1, 2); current guidelines recommend parenteral antibiotics for cases with
complicated disease(3). Sepsis has been identified as a major contributor of death in
children with SM and is associated with both early and late case fatality(4, 5). Because
of limited diagnostic resources and facilities in developing countries, rapid tests to
identify high-risk children are needed to enable supportive interventions to be targeted
effectively and improve current management guidelines.
Whilst urinary tract infections (UTIs) are said to be a common complication in SM
reported prevalence varies between 3% and 35% among paediatric admissions with
malnutrition(6-8). UTIs are caused predominantly by Gram-negative enteric bacilli. The
increased susceptibility of malnourished children to UTIs is thought to be due to their
transient state of immunodeficiency characterized by breakdown of anatomical barriers,
decreased cell-mediated immunity, decreased phagocytosis and opsonization. (9-11). It
is postulated that these factors allow organisms to ascend up the urinary tract, and may
lead to secondary invasive bacterial sepsis. The World Health Organization
recommends urine microscopy and culture to diagnose UTI(3). Urine culture is not
practical as it takes at least 48 hours to give a result whilst microscopic examination of
urine is time consuming and labor intensive. Moreover, with a deliberate shift to
community-based management of severe malnutrition(12), performing microscopy and
culture is not practical.
Dipstick urinalysis is an excellent, low-cost, bedside screening test in children. It is used
to screen for urinary tract infections (nitrites and leucocyte esterase), diabetes mellitus
(glucose), nephrotic syndrome (protein), glomeluronephritis (blood) to guide diagnostic
work-ups and for assessment of hydration status (specific gravity). Reagent strips
perform as well as microscopy in the diagnosis of urinary tract infection in many patient
groups, including children (13, 14) . Despite concerns of the specificity and thus
diagnostic accuracy, studies have shown that a strategy that combines use of nitrites
and leucocyte esterase (LE) testing appears to offer the best performance(15). Nitrites
(a bacterial metabolite of dietary nitrate) and leucocyte esterase (from white cells) are
not normally present in sterile urine. A negative test gives a negative predictive value
(NPV) of 97% (specificity 98.7%)(14, 16, 17). Positive results identify the group
requiring urine culture and may help target first-line treatment.
From the studies in developing countries that have looked at UTI in malnourished
children, none have examined the usefulness of dipstick screening of urine specimens
or explored its prognostic value. In this study we sought to establish if the presence of
LE and nitrites in urine correlates with disease severity and fatal outcome in
malnourished children.
PATIENTS AND METHODS
Study site
A large prospective, observational study conducted at Kilifi District Hospital paediatric
ward at the Centre for Geographical Medicine Research, on the coast of Kenya
between June 2005 and June 2007.
Ethical approval was granted by the Kenya
Medical Research Institute (KEMRI) Scientific Steering Committee and the National
Ethics Review Committee (SSC No 927).
Patients and consent
All children referred to the general paediatric ward for admission were assessed for
eligibility. At admission, the admitting clinician completed a standardised medical case
report form documenting medical history and physical examination. Ward assistants
were trained to take anthropometric measurements (height, weight and mid-upper arm
circumference) on all children. Following an explanation of the study in the local
language, written consent was sought from parents or guardians. Children received
routine standard of care specified by the WHO guidelines(3). This included parenteral
antibiotics (ampicillin and gentamicin), a broad-spectrum anti-helminth (mebendazole),
therapeutic milk (F75 initially then F100) and vitamin and mineral supplementation.
Urine testing
Ward assistants were trained to collect urine samples. Urine was collected as soon as
possible after admission through clean catch method. Dipstick testing was done on a
freshly voided urine sample using urinalysis reagent strips (Mission™, Acon
Laboratories Inc, San Diego, USA). If the urine was positive for leukocytes or nitrites, a
further clean catch urine sample was sent for microscopy, culture and sensitivities. This
two stage method has been shown to reduce the possibility of false positive results by
contamination(18). Only urine samples collected on the day of admission were reported.
Laboratory methods
Urine was cultured on CLED agar at 370C. A positive culture was defined as growth of a
single urinary tract pathogen at >= 50 CFU/µL. As part of routine clinical practice, blood
cultures were taken at admission and incubated in a BACTEC 9050 system instrument
(Becton Dickinson, http://www.bd.com). Sensitivities to antimicrobials were investigated
in accordance with the recommendations of the British Society for Antimicrobial
Chemotherapy (BSAC).
All the clinical and laboratory data was maintained in a
database (FileMaker 5.5v1, FileMaker Inc, www.filemaker.com).
Definitions
Severe malnutrition was defined as one of: oedema of both feet (of kwashiorkor or
marasmic kwashiorkor) or weight for height Z score ≤ -3 or mid upper arm
circumference (MUAC) < 11cm (if length > 65cm)(19). A positive dipstick was defined
as either leucocyte esterase ≥ (+/-) or nitrites ≥ (+).
Statistical Methods
We categorised children into two groups for analysis; LE or Nitrites positive (positive
dipstick) and both LE and Nitrite negative (negative dipstick). Measures of association
between the groups were evaluated using a Pearson’s chi-square test of association
and Fisher’s exact for small samples. Comparison of means was done using the
unpaired Students t-test for continuous data.
We performed survival analysis to
determine the probability of survival in days following admission and assessed the
difference in the survival functions using the logrank test. Both known and potential risk
factors for poor outcome in SM were evaluated by fitting the Cox proportional hazards
model assuming that the baseline force of mortality remains constant over the entire
study period in the two groups. Statistical significance was assessed at the 5% level
with p-values < 0.05 considered to be statistically significant.
RESULTS
Patient Characteristics
Six hundred sixty seven children (313 females) were included in the study. The median
age was 22 months (IQ range 16-35 months). Two hundred and thirty nine (36%) had
oedema. Of all children recruited, 498(75%) gave a urine sample at admission, and
before parenteral antibiotics. Out of 667 children enrolled into the study, 125 children
(19%) died in hospital during the two year study period.
Dipstick results
Of the 498 admission urine sample obtained, 88(18%) were LE positive, 53(11%)
nitrites positive, 111(23%) protein positive and 24(5%) blood positive. Only 22(4%) were
positive for both LE and nitrites while 119(24%) positive for either. A higher proportion of
girls had nitrites positive (14% vs. 8%, P=0.02), leucocytes positive (26% vs. 11%,
P<0.01) and blood positive (7% vs. 3%, P =0.02) samples compared to boys but no
significant differences in protein. Only protenuria showed a difference in frequency by
age, being more common in the infants compared to those older than 1 year (44% vs.
21%, P< 0.001).
Urine culture of 119 samples yielded 28 organisms, all of them coliforms. Of the
isolates, 26(93%) were resistant to cotrimoxazole, 12(43%) to gentamicin, 4(14%) to
nalidixic acid and 6(21%) to nitrofurantoin. Blood culture yielded E. coli from one patient,
contaminants in four while the remaining 23 had no isolate. Resistance to the current
standard treatment was not related to age, gender or outcome (death). There was no
association between a positive urine dipstick and bacteraemia (5% vs. 7%, P= 0.54).
Case fatality
Children with no urine sample collected on admission were more severely ill and had
greater case fatality (Table 1).They were more likely to have features of severe disease
namely shock, impaired consciousness and bacteraemia with nine (20%) of these
children died within 48 hours of admission. Forty two percent of those who died had a
positive urine dipstick. In-patient fatality was 30(26%), 8(34%), 14(26%) and 25(28%)
for protein, blood, nitrite and LE respectively. Children with LE or Nitrite positive had a
higher fatality compared to those with negative dipstick (29% Vs 12%, P<0.01). The
proportions of children with features of severe disease at admission were compared
between the two groups (dipstick positive and dipstick negative) but did not show any
significant differences (Table 2) except for hypokalemia. There was no association
between a positive urine culture and death (19% vs. 23%, P= 0.57).
The in-hospital survival functions (probability of survival) were compared in dipstick
positive and dipstick negative children which demonstrated a significant difference
between the two groups (P<0.01). Cox analysis also determined that a positive urine
dipstick was independently associated with death, even after consideration of baseline
variables (HIV status, level of consciousness, dehydration, impaired perfusion,
electrolyte imbalance and bacteraemia) known to affect outcome in SM (table 3).
Children who had a positive dipstick results had nearly three times higher risk of dying
than those who had a negative dipstick result (HR = 2.76 95% CI: 1.62 -4.69, P < 0.01).
The risk of dying was 2.3(95% CI: 1.31-4.09, P= 0.003) and 1.8(95% CI: 1.10-4.50, P=
0.067) for children with LE and nitrites respectively. There was no difference in the
median time to death between the two groups (7.5 days vs. 6days, p =0.627).
DISCUSSION
In this study, approximately a quarter of the 498 children tested had a positive urine
dipstick. Children who had a positive dipstick results were approximately three times
more at risk of dying than those who had a negative dipstick result even after adjusting
for known features of severe disease: bacteraemia, shock, electrolyte imbalance and
impaired consciousness(5, 20, 21). Forty two percent of all children who died were
dipstick positive. Overall, 6% of the children had culture proven UTI, with enteric
coliforms being the predominant organism isolated. Most of the isolated organisms had
poor sensitivity to antibiotics commonly used in malnutrition; 40% were resistant to
gentamicin and 90% resistant to cotrimoxazole.
Our findings of high resistance patterns to the current standard of care for SM confirms
previously reported low sensitivity to first line antibiotics (7, 22). While this could have
been due to prior use of antibiotics as have been reported previously (23), these findings
are
worrying . Poor sensitivity to antibiotics commonly used in malnutrition may
contribute to both primary failure and later failures due to recrudescence of inadequately
treated pathogens. This supports the need for surveillance of antimicrobial resistance
patterns to advice on applicable recommendations on antimicrobial use in UTIs.
To the best of our knowledge, no previously published study has described mortality
according to dipstick finding. We could not find any association between urine dipstick
and bacteraemia but blood cultures are known to be insensitive for detecting bacteremia.
We postulate that since malnourished children have relative immunosuppresion due to
nutritional factors and/or active immunosuppresion due to HIV or TB, they are at risk
invasive bacterial sepsis secondary to inadequately treated pathogens. The high
mortality and poor sensitivity to routine antibiotics in the background relative
immunosuppresion prompts the need for clinical trials to determine if changes in the
current first line therapy would improve outcome in children with UTI or in whom UTI is
suspected (e.g. positive urine dipstick).
The choice of routine antibiotics should be guided not only by the susceptibility of likely
pathogens, but also by the sites of infection, the ability of the antibiotics to penetrate the
sites and immune response of the host. Children with severe malnutrition are susceptible
to both skin and urinary tract infection suggesting the need for antibiotics with good tissue
penetration and good renal excretion. Though combinations of beta-lactams and
aminoglycosides are excellent first line therapy, consideration should be given to
fluoroquinolones since they possess an enlarged antimicrobial spectrum, greatly
enhanced bactericidal activity, and substantial pharmacokinetic advantages compared
to nalidixic acid. Due to safety concerns and limited published experience of their use,
quinolones use in children is limited to life-threatening or difficult to treat infection and
circumstances where other antibacterial agents cannot be used. (24, 25). Results of
published clinical trials with fluoroquinolones in pediatric patients show promising
efficacy and safety and may be of benefit to children with severe malnutrition (4) but
pharmacokinetic studies are required first.
One of the limitations of our study was the challenges we encountered when collecting
urine in severely ill children. We may have underestimated the true prevalence of UTI
and prognostic value of urine dipstick since we were unable to collect urine in a quarter
of the children. Most of these cases were severely ill, either in shock or had depressed
level of consciousness. Catheter urine specimen has been used in pediatric ICU setting.
However it is expensive and always poses the risk of introducing infection. Urine
collection by means of adhesive perineal bag is a widely used method in children who
cannot control urine emission. It is cheap and easy to use(26). However, this technique
has a high risk of contamination and a very low positive predictive value(27). In poor
resource setting it would be worthwhile to evaluate its utility when proper cleaning of the
perineal area before urine collection is done as this has been shown to reduce the
contamination rate(28). Our interpretation of the data was also limited by selective urine
culture and prior antibiotic use which may underestimate prevalence of UTIs and
increase antimicrobial resistance.
Given the high mortality observed in malnourished children especially those with
bacteraemia, there is need to identify simple and robust technologies for rapid diagnosis
of the potential foci of infection. An ideal screening test should be inexpensive, easily
accessible and simple to do. In this regard, dipstick urinalysis fares well. A single
reagent strip costs $0.15 compared to $4 for urine microscopy. Although not very
specific in diagnosing UTIs, it identifies children at a very high risk of dying and is thus a
useful in SM.
Conclusion
The results of the dipstick urinalysis suggest that they can be utilized as a valuable
prognostic marker among children admitted to hospital with SM. Use of dipstick
urinalysis in SM will help identify children at high risk and may help in deciding
appropriate treatment. Clinical trial are needed to determine appropriate first line therapy
in children with SM.
Author Contributions
NT, AT and JK provided inpatient care and data collection. EO, JB and NT conducted
analysis and preparation of the manuscript for submission. KM conceived and designed
the study, conducted the statistical analysis and the overall manuscript preparation. All
authors contributed to the final manuscript.
Acknowledgements
We are grateful to the subjects for their participation in the study. We are also grateful to
all members of the KEMRI laboratory and computing team who participated in data
collection and data storage. The study was supported by the Kenya Medical Research
Institute and the Wellcome Trust. JB is supported by a fellowship from the Wellcome
Trust. This paper is published with the permission of the Director of the Kenya Medical
Research Institute (KEMRI).
Conflicts of interests
The authors have no potential conflict of interest to declare.
Role of the funding source
The sponsor of the study had no role in study design, data collection, data interpretation
or writing of the report.
WHAT IS ALREADY KNOWN ON THIS TOPIC
Severe malnutrition is associated with high mortality; however there are very few rapid
tests that can identify high risk children. Dipstick urinalysis is used as a screening test
for UTIs in children, a condition that is common in severely malnourished children.
WHAT THIS STUDY ADDS
Dipstick urinalysis in children with severe malnutrition identifies children at high risk of
dying and can be used to stratify patients for interventions with antibiotics.
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Table 1: Clinical and laboratory features of those who provided an admission urine
sample and those who did not.
Variable
Dipstick (%) 1
No Dipstick (%)
P value
Patients recruited, n
Female
Age – Median (IQR)
Oedema
Clinical signs
Fever(temperature >38.5C)
Hypothermia (temperature <36.0C.)
Tachypnoea4
Tachycardia 3
Hypoxia (oxygen saturations <90%)
Impaired consciousness2
Severe anaemia (Hb <5 g/dl)
Severe dehydration
Impaired perfusion6
SIRS5
Laboratory features
Hyponatremia (sodium<130mmol/l)
Hypokalemia (potassium<3.0mmol/l)
Bacteraemia
Leucocytosis(WBC count > 12000/mm3)
HIV antibody positive
Median days in stay(IQR)
Died
Died within 48hrs
498
227(46)
22.4(17-36)
178(36)
169
86(51)
20.9(14-31)
61(36)
0
0.26
0.23
0.97
197(40)
0
115(23)
137/497(28)
73/497(15)
11(2)
160(32)
101(20)
76(15)
220(44)
72(42)
2(1)
51(30)
53(31)
36(21)
17(10)
52(31)
41(24)
44(26)
95(56)
0.52
0.06
0.07
0.37
0.05
<0.001
0.08
0.29
0.01
0.01
236/429(55)
155/429(36)
31(6)
461/489(94)
107/478(22)
9 (7-14)
81(16)
6(1)
82/146(56)
44/146(30)
21(12)
159/164(94)
36/162(21)
10 (7-14)
44(26)
9(5)
0.81
0.19
0.01
0.86
0.62
0.26
<0.01
<0.01
1Values
in parentheses are percentages.
consciousness =prostration or coma.
3Tachycardia = heart rate > 180, 140, 130 bpm for ages < 12m, 1-5 y, > 5 y respectively.
4Tachypnea =respiratory rate above 50, 40 or 30 bpm for ages < 12m, 1-5 y, > 5 y respectively.
5Severe inflammatory response syndrome(SIRS)= at least two of the following: Core temperature of
>38.5C or <36.0C; or tachycardia ; or tachypnea; or leucocytosis, or white blood cell count less than
4,000/cu mm(29)
6Impaired perfusion: any one of the following; Capillary refill time >2 sec or temperature gradient or weak
pulse volume
2Impaired
Table 2: Selected features of severe disease in dipstick positive and dipstick negative
children
Clinical variables
No of patients, n
Female
Dipstick
Positive 1
119
72(61)
Dipstick
Negative
379
155(41)
P value
Male
46(39)
225(59)
Median age (IQR)
21(15-31)
23(16-36)
0.14
Oedema
50(42)
128(34)
0.10
HIV antibody positive
25/113(22)
90/365(25)
0.52
Fever (temperature >38.5C)
45(38)
152(40)
0.66
Tachypnoea 4
24(20)
90(24)
0.37
26/118(22)
111/379(29)
0.12
19/118(16)
54/379(14)
0.62
3(2)
8(2)
0.73
Severe dehydration
29(24)
72(19)
0.20
Severe anaemia(Hb <5 g/dl)
33(28)
127(32)
0.24
Impaired perfusion5
16(13)
60(16)
0.53
SIRS
48(40)
172(45)
0.33
Hyponatremia (sodium<130mmol/l)
64/104(60)
172/325(53)
0.12
Hypokalemia (potassium<3.0mmol/l)
48/102(47)
107/327(33)
<0.01
Bacteraemia
6(5)
25(6)
0.67
Leucocytosis(WBC count > 12000/mm3)
113/118(96)
348/371(94)
0.50
Died (%)
34(29)
47(12)
<0.001
Died within 48hrs
3(2)
3(1)
0.15
<0.001
Clinical signs
Tachycardia
3
Hypoxia (oxygen saturations <90%)
Impaired consciousness
2
Laboratory features
1Values
in parentheses are percentages.
consciousness =prostration or coma.
3Tachycardia = heart rate > 180, 140, 130 bpm for ages < 12m, 1-5 y, > 5 y respectively.
4Tachypnea =respiratory rate above 50, 40 or 30 bpm for ages < 12m, 1-5 y, > 5 y respectively.
5Severe inflammatory response syndrome(SIRS)= at least two of the following: Core temperature of
>38.5C or <36.0C; or tachycardia ; or tachypnea; or leucocytosis, or white blood cell count less
than 4,000/cu mm(29)
6Impaired perfusion: any one of the following; Capillary refill time >2 sec or temperature gradient or
weak pulse volume
2Impaired
Table 4. Hazard Ratio for death in Children with Malnutrition according to dipstick results
Dipstick Results
None
Any
LE
Nitrates
Blood
Protein
LE or Nitrates
LE or Blood
Odds
Ratio
1.0
Interval)*
2.0(1.1-3.6)
2.0(1.0-4.5)
1.5(0.7-3.2)
1.7(0.7-4.7)
1.5(0.8-2.8)
2.5(1.3-4.5)
1.8(0.9-3.30
(95%
Confidence
*Odds ratios are for death, adjusted for age, sex, HIV infection, severity and type of
malnutrition, electrolyte imbalance and dehydration.
Figure 1: cumulative hazard curve grouped by dipstick results
0.30
Cumulative hazard curve grouped by dipstick results
0.00
0.10
0.20
Logrank P value<.001
Adjusted* HR 2.76(95% CI 1.62-4.69)
Dipstick positive
0
10
20
30
Time from admission(days)
Dipstick negative
40
* The Hazard ratio has been adjusted for sex, age, HIV status, level of consciousness, dehydration,
impaired perfusion, hyponatremia, hypokalemia and bacteraemia.