h5n1 Oxford Journal

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© The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e‐mail: [email protected]

H5N1 Avian Influenza in Children

Ahmet Faik Oner,1 Nazim Dogan,2 Viktor Gasimov,3 Wiku Adisasmito,4 Richard Coker,5 Paul K. S. Chan,7

Nelson Lee,7 Owen Tsang,8 Wanna Hanshaoworakul,9 Mukhtiar Zaman,10 Ebun Bamgboye,11 Anna

Swenson,12 Stephen Toovey6 and Nancy A. Dreyer12

1Yuzuncu Yil University, Van, and 2Ataturk University Medical School, Erzurum, Turkey; 3Azerbaijan

Ministry of Health, Baku, Azerbaijan; 4University of Indonesia, Depok, Indonesia; 5London School of

Hygiene and Tropical Medicine, and 6Royal Free and University College Medical School, Department of

Infection and Immunity, Academic Centre for Travel Medicine and Vaccines, London, United Kingdom;

7Faculty of Medicine, Chinese University of Hong Kong; 8Princess Margaret Hospital, Hong Kong,

SAR;9Ministry of Public Health, Nonthaburi, Thailand; 10Khyber Teaching Hospital, Peshawar, Pakistan;

11St Nicholas Hospital, Lagos, Nigeria; 12Outcome Sciences, Inc, Cambridge, Massachusetts

Corresponding Author: Dr. Nancy A. Dreyer, Outcome Sciences, 201 Broadway, Cambridge, MA, 02139

([email protected])

Alternate Corresponding Author: Dr. Stephen Toovey, Royal Free and University College Medical School,

Department of Infection and Immunity, Academic Centre for Travel Medicine and Vaccines, London,

United Kingdom, ([email protected])

Clinical Infectious Diseases Advance Access published March 15, 2012 by guest on A

ugust 11, 2015http://cid.oxfordjournals.org/

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Key Points : A patient registry, representing the largest global knowledge base on clinical presentation

and case fatality for confirmed cases of avian influenza, shows that most pediatric cases who present

with rhinorrhea survive this infection, regardless of country and antiviral treatment.

by guest on August 11, 2015

http://cid.oxfordjournals.org/D

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Abstract

Background. Avian influenza continues to pose a threat to humans and maintains the potential for

greater transmissibility. Understanding the clinical presentation and prognosis in children will help

guide effective diagnosis and treatment.

Methods. A global patient registry was created to enable systematic collection of clinical, exposure,

treatment and outcomes data on confirmed cases of H5N1. Bivariate and multivariate statistical tools

were used to describe clinical presentation and evaluate factors prognostic of survival.

Results. Data were available from 13 countries on 193 cases <18 years who were confirmed as having

been infected with H5N1; 35.2% of cases were from Egypt. The case fatality rate (CFR) for children was

48.7%, with Egypt having very low pediatric CFR. Overall, children aged < 5 years had the lowest CFR

and were brought to hospital more quickly and treated sooner than older children. Pediatric cases who

presented for medical care with a complaint of rhinorrhea had a 76% reduction in the likelihood of

death compared with those who presented without rhinorrhea, even after statistical adjustment for age,

having been infected in Egypt, and oseltamivir treatment (P=0.02). Delayed initiation of treatment with

oseltamivir increases the likelihood of death, with an overall 75% increase in the adjusted odds ratio for

death for each day of delay.

Conclusions. The presence of rhinorrhea appears to indicate a better prognosis for children with H5N1,

with most cases surviving regardless of age, country, or treatment. For cases treated with oseltamivir,

early initiation of treatment substantially enhances the chance of survival.



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H5N1 Avian Influenza in Children

Background

Although much of the attention on influenza has diminished, especially since the relatively mild

pandemic of H1N1 swine flu, H5N1 avian influenza continues to occur, with human cases continuing to

be reported in 2011 [1,2]. A large and ineradicable avian reservoir for this infection means that it may

re‐emerge as an important threat to human health in many countries [3], with a number of clades of

possibly differing virulence circulating in different regions [4]. This paper describes the clinical

presentation including identification of prognostic factors and treatment effectiveness for children

infected with laboratory confirmed influenza H5N1.

Methods

This investigation utilized the global avian influenza registry, with 391 cases of laboratory confirmed

influenza A (H5N1). Using standard definitions and data collection procedures, information was

gathered from medical records, clinical and field investigations including government sources, and from

published case reports. Information was sought about presenting symptoms, treatments and survival.

The registry methods are described in full elsewhere [5].

Cases were recorded as having occurred from 1997 through 2010. The eighteen earliest cases were

from the initial 1997 outbreak, before World Health Organization (WHO) certified laboratory

confirmation was available. Of the remaining 373 cases, 358 (96%) had laboratory confirmation from a

WHO‐accredited laboratory and 15 (4%) were confirmed by a local laboratory.

Nearly half of the cases (193/391) were younger than 18 years at the time of diagnosis. Pediatric cases

were recorded from 11 countries: Azerbaijan (5), Bangladesh (1), Cambodia (3), China (6), Egypt (68),

Hong Kong (11), Indonesia (59), Laos (1), Thailand (13), Turkey (12) and Vietnam (14). Pediatric cases



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are further categorized as aged 0‐5 years (n=91, including a single case aged less than one year), 6‐11

years (n=46), and 12‐17 years (n=56).

Statistical methods

Differences in categorical variables by age group were examined using chi‐square or Fisher’s exact tests.

Differences in continuous variables by age group were compared using the non‐parametric Wilcoxon

rank‐sum and Kruskal Wallis tests since the data were not normally distributed. A P‐value less than 0.05

was considered statistically significant. A Bonferroni correction was used to account for multiple

comparisons between the various age groups; the overall alpha level of 0.05 was divided by the number

of comparison to give the alpha level considered statistically significant for multiple comparisons.

Relative risks and associated 95% confidence intervals are also presented. A multivariate logistic

regression approach was used to examine the odds of death for cases with and without rhinorrhea while

controlling for age, country (Egypt versus others) and oseltamivir treatment [6,7]. The small number of

cases did not allow for addition of potential confounders other than oseltamivir, age and country. Two

models were used: one included all cases with information recorded about the presence or absence of

rhinorrhea (n=100), and the other included only cases who had both information about the presence or

absence of rhinorrhea and who were treated with oseltamivir (n=44).

Results

Table 1 shows the distribution of cases by age group and country, and the corresponding case fatality

rates (CFR) for all age groups. The overall CFR for pediatric cases was 48.7% in contrast to the overall

CFR of 57.5%, with substantial variability by age and country. Young children are more likely to survive

than older children and adults, with children aged ≤5 years showing a markedly lower CFR (28%) than



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older cases (p <0.01 for all comparisons). The CFR for those aged 6‐11 years was also lower than that of

those aged 12‐17 years (p=0.003).

Children aged ≤5 years were brought for medical attention, hospitalized, and treated with antivirals

earlier than older children, with a median of 3 days from symptom onset to start of treatment in the 0‐5

year age group versus 7 days for older groups (p=0.01, see Table 2). The time from symptom onset to

antiviral treatment was similar for cases aged 6‐11 years and those aged 12‐17 years, despite the much

higher mortality rate in the 12‐17 age group. The median of 9 days from symptom onset to death was

virtually identical for all ages.

There were some differences by age group in symptoms reported at first presentation for medical care

(Table 3). Young children (≤5 years) reported rhinorrhea more frequently, and headache and myalgia

less frequently, than older children and adults. Headache was a much more frequent complaint on

presentation for those aged 12‐17 years than all other age groups (p<0.01). Bleeding gums were

reported more frequently for ages 6 through 17, though these findings are based on especially small

numbers.

With respect to whether any particular signs, symptoms or tests carry prognostic value for survival from

avian influenza during the first 24 hours of hospital admission, children who died were more likely to

have had decreased leukocyte, lymphocyte and platelet counts, and to have had elevated alanine

aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, and hematocrit values; children

who survived were more likely to have had lower hemoglobin levels (Table 4). Creatine kinase and

lactate dehydrogenase levels at presentation for medical care did not show statistically significant

relationships with likelihood of survival, but small numbers counsel caution in interpretation.

Examination of the many clinical signs and symptoms reported at presentation for medical care, shown

in Table 5, demonstrated that the presence of rhinorrhea is associated with a decreased risk of death,



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especially for children aged ≤5 years (RR of death for cases with rhinorrhea = 0.13; 95% CI 0.03, 0.53).

Also, the non‐specific symptom characterized as “unexplained respiratory illness with cough, shortness

of breath, or difficulty breathing” appears to carry some prognostic value, showing a decreased risk of

death, particularly in children ≤5 years. Similarly, four other symptoms (diarrhea, headache, fatigue or

malaise, and myalgia) also showed some weak but consistent evidence that they may be associated with

a better prognosis in children. Other symptoms, including fever, excessive sputum production, sore

throat, vomiting, and tachypnea, did not show any consistent relation to the likelihood of death.

Although small numbers preclude examination of specific age groups, we investigated whether the

improved survival among cases who presented with rhinorrhea might have been due to their having

received medical attention sooner or having been treated more quickly than children who did not

present with these symptoms. For children who presented with rhinorrhea, the time to presentation for

medical care was not very different (median of one vs. three days) for cases who survived and died (n=9

cases with information on time from symptom onset to presentation for medical care, p=0.45).

However, children with rhinorrhea who survived were treated more quickly with antivirals (median of

2.5 days from symptom onset to start of antivirals) than those who died (median of 10 days, n=17 cases

with information on time from symptom onset to treatment with antivirals, p<0.01). Using multivariate

modeling, children who presented with rhinorrhea had 76% reduction in the risk of death (OR 0.24, 95%

CI 0.08, 0.77) when simultaneously controlling for oseltamivir treatment, country, and age group (Table

6). Looking only at children prescribed oseltamivir, however, the survival benefits associated with

rhinorrhea were still remarkable, but did not achieve statistical significance (OR 0.38, 95% CI 0.03, 5.55).

Looking at time to initiation of treatment with oseltamivir, there was an increased odds of death for

each day of delay (OR 1.75, 95% CI 1.17, 2.61) when controlling for age, rhinorrhea and country (Egypt).



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Discussion

The clinical presentation of avian influenza in children differs in some meaningful ways from that in

adults. Unlike some earlier reports that characterized H5N1 infections as carrying a higher mortality in

children, the lower mortality rate in children aged ≤5 years in this large case series is quite striking,

especially since the survival benefit is evident even when type of presenting symptom, antiviral

treatment, time to treatment initiation and country are taken into account [8,9]. Of note, using a small

series from Vietnam (N=36), Kawachi et al reported that children aged 6 years were at higher risk of

fulminant disease with acute respiratory distress syndrome (ARDS) than younger children [10]. It might

be that the less mature systems of younger children mount an immune response less harmful to their

hosts.

The presence of rhinorrhea at presentation is more common in children aged ≤5 years, and appears to

be associated with a markedly decreased risk of death in this age group. This symptom appears to have

prognostic value, even after accounting for the most obvious explanations for the increased survival

seen in children with this presentation, such as having been seen sooner or having received their first

dose of antiviral early in the course of their illness, or coming from Egypt, which has a lower CFR than

other countries [6,7]. In this registry, 35% (68/193) of the cases under 18 years of age were from Egypt,

as were more than half (52%, 47/91) of the cases aged ≤5 years. However, the protective effect of

rhinorrhea was still evident in the 0‐5 year age group, when tested both by excluding Egyptian cases

from analysis and by using statistical analyses to control simultaneously the effects of country (see

Model One in Table 6, the only model which had enough cases to permit inclusion of Egypt as an

additional covariate). Thus, there remains an intriguing difference in the frequency of rhinorrhea as a

presenting symptom and its apparent prognostic value, which declines with increasing age. One might

speculate that this represents primary inoculation of the virus into the upper rather than the lower



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airways, or perhaps a less injurious pathway to immune activation [11]. Regardless of the explanation,

there remained benefit from early antiviral use. Asymptomatic and mild cases of H5N1 have been

previously reported, and one might speculate that cases presenting with rhinorrhea represent a subset

of patients with generally milder or illness [12].

The recording of other symptoms may not be as reliable as rhinorrhea, which can be observed by the

clinician. For example, the paucity of myalgia as a presenting symptom in children aged 0‐5 years may

simply reflect the inability of young children or their parents to accurately report this symptom, rather

than a true difference in symptom occurrence by age.

Our findings with respect to laboratory values might possess some clinical utility, indicating severity to

clinicians, and suggesting the need for aggressive antiviral and supportive therapy. Our findings are

consistent with others. Grose et al reported leukopenia and thrombocytopenia in Vietnamese and Thai

children suffering from H5N1 infection [9]. Examining Vietnamese pediatric H5N1 cases with ARDS,

Kawachi et al reported leukopenia and thrombocytopenia to be predictors of fulminant disease with

ARDS [10]. Furuya et al, in their meta‐analysis of published pediatric H5N1 case series, found

thrombocytopenia and leukopenia to be significantly associated with mortality [13]. Pediatric registry

cases who died confirmed these findings with respect to leukopenia; registry cases that suffered a fatal

outcome also demonstrated a lower median thrombocyte count within the first 24 hours of admission, if

not always a true thrombocytopenia. This might suggest a falling or relatively low thrombocyte count

could be a very early pointer to severe disease and poor outcome. Leukopenia and thrombocytopenia

are not infrequently seen in other very severe infections, for a variety of reasons including consumption,

peripheral sequestration, and myelosuppression.

Furuya et al also reported that a raised peripheral blood AST level trended to significant association with

mortality [13]; that association was confirmed in this larger patient registry dataset. Further, our data



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also revealed a significant association between a raised ALT level and mortality in children. These

findings most likely represent widespread cellular, and in particular hepatocyte, insult consequent upon

the severe inflammatory processes that accompany advanced H5N1 infection [14].

The raised hematocrit seen in fatal cases could be due to a degree of hemoconcentration possibly

associated with dehydration and perhaps with vascular injury occasioned by the severe inflammatory

processes known to accompany H5N1 infection; the lower mean hemoglobin levels seen in survivors

could accord with the haemoconcentration seen in fatal cases.

With respect to antiviral treatment, by far the most frequently used antiviral in registry cases was

oseltamivir (91% of all antivirals), and these data continue to show the benefits of early treatment with

oseltamivir. We also tested the generalizability of this finding by looking at data from the two countries

with the most cases, Egypt and Indonesia, and comparing antiviral effectiveness data between them and

the rest of the countries in the registry. As country of infection (and illness) is a variable that likely

reflects the relative virulence of the circulating strain as well the sophistication and accessibility of the

local health care system, we controlled by ‘country’ rather than by viral strain or clade, even though the

latter might well indicate relative virulence [15,16].

The median number of days from symptom onset to antiviral treatment was markedly shorter for

surviving cases compared to fatal cases for all pediatric age groups, regardless of country. These

findings confirm once again the importance of early initiation of effective antiviral therapy in human

H5N1 infection [5], and specifically in the pediatric setting.

Overall, the data from this registry show that children aged ≤5 years are more likely to survive infection

with H5N1; they come to medical attention more quickly than adults, and receive antiviral treatment

more quickly than their older counterparts. The results also support the prognostic value of some



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laboratory findings on presentation as well the value of antiviral therapy, especially when initiated early

in the course of infection.

Many limitations to the analysis and interpretation of these data remain, some due to data that were

not available or tests that were either not performed or not recorded, and others, to the relatively small

numbers of cases available for analyses. However, it should be recognized that this represents the

largest collection of aggregated clinical data on avian influenza in humans, all of whom have laboratory

evidence confirming infection with H5N1. These data may provide insights to clinicians treating

pediatric cases, and meaningful clues to immune response that can be harnessed for more effective

treatment of this highly lethal disease.

Funding

This work was supported by a contract to Outcome Sciences, Inc., from F. Hoffmann‐La Roche. The

sponsor provided scientific collaboration and had rights to nonbinding review of manuscripts but did not

have the right to decide whether papers should be submitted for publication, to choose authors, or to

approve the wording of any manuscripts.



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Acknowledgements: None

Potential Conflicts of Interest

W.A., M.Z., A.F.O., E.B., and N.D. received modest support to facilitate data collection and review. R.C.

has received funding from F. Hoffmann‐La Roche, the manufacturer of oseltamivir. P.K.S.C. and N.L.

received funding support from F. Hoffmann‐La Roche for an investigator‐initiated study. N.A. D. and A.S.

are employed by Outcome Sciences, Inc., a private company that specializes in patient registries and

which received funding from F. Hoffmann‐La Roche to create and conduct the registry study. S.T. is a

former employee and a paid consultant to F. Hoffmann‐La Roche and has been reimbursed by a number

of influenza vaccine manufacturers.



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ndex.html. Accessed 27 Sep 2011.

(3) Suarez DL. Avian influenza: our current understanding. Anim Health Res Rev 2010 Jun;11(1):19‐

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(8) Areechokchai D, Jiraphongsa C, Laosiritaworn Y, eat al. Investigation of avian influenza (H5N1)

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(16) Govorkova EA, Ilyushina NA, Boltz DA, Douglas A, Yilmaz N, Webster RG. Efficacy of oseltamivir

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Table 1. Case Fatality Rate by Country and Age Group

Pediatric cases

Country 0‐5 years 6‐11 years 12‐17 years All

Pediatric

All Ages

Azerbaijan NA 0/1

(0.0%)

2/4

(50.0%)

2/5

(40.0%)

6/9

(66.7%)

Bangladesh 0/1

(0.0%)

NA NA 0/1

(0.0%)

0/1

(0.0%)

Cambodia 1/1

(100.0%)

1/1

(100.0%)

1/1

(100.0%)

3/3

(100.0%)

6/6

(100.0%)

China NA 2/6

(33.3%)

NA 2/6

(33.3%)

16/28

(57.1%)

Egypt 2/47

(4.3%)

2/11

(18.2%)

5/10

(50.0%)

9/68

(13.2%

34/106

(32.1%)

Hong Kong 1/8

(12.5%)

0/1

(0.0%)

1/2

(50.0%)

2/11

(18.2%)

6/18

(33.3%)

Indonesia 16/21

(76.2%)

11/14

(78.6%)

22/24

(91.7%)

49/59

(83.1%)

107/124

(86.3%)

Laos NA NA 1/1

(100.0%)

1/1

(100.0%

1/1

(100.0%)

Nigeria NA NA NA

NA

1/1

(100.0%)



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Pakistan NA NA NA

NA

¼

(25.0%)

Thailand 2/4

(50.0%)

5/6

(83.3%)

3/3

(100.0%)

10/13

(76.9%)

17/25

(68.0%)

Turkey 0/6

(0.0%)

1/3

(33.3%)

3/3

(100.0%)

4/12

(33.3%)

4/13

(30.8%)

Vietnam 3/3

(100.0%)

2/3

(66.7%)

7/8

(87.5%)

12/14

(85.7%)

26/55

(47.3%)

Total 25/91

(27.5%)

24/46

(52.2%)

45/56

(80.4%)

94/193

(48.7%)

225/391

(57.5%)



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Table 2. Time Course of Illness from Onset of Symptoms to Antiviral (AV)

Treatment and Death, By Age (N=391)

Median Days from Symptom Onset to:

Age Case Fatality

Rate

Presentation for

Medical Care

Hospitalization� AV Treatment�

(N= 242 treated)

Death

(N=225 fatal)

Years N* Median

(min‐max)

N* Median

(min‐max)

N* Median

(min‐max)

N* Median

(min‐max)

0‐5 25/91 (27.5%) 31 0 (0‐20) 85 3 (0‐20) 33 3 (0‐11) 24 9 (3‐17)

6‐11 24/46 (52.2%) 28 2 (0‐9) 44 4.5 (0‐25) 20 7 (2‐21) 22 10.5 (2‐32)

12‐17 45/56 (80.4%) 34 1 (0‐10) 55 5.0 (0‐13) 24 7 (1‐14) 44 9 (3‐31)

All

Ages

225/391

(57.5%)

193 1 (0‐20) 374 5.0 (0‐25) 170 6 (0‐23) 215 9 (2‐32)

� Medians are significantly different between age groups.

*Total N differs according to completeness of timing data.



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Table 3. Frequency of First Symptoms Reported at Medical Care by Age

Age in Years Symptom

At Presentation

for Medical Care N 0‐5 6‐11 12‐17 >18 P‐value*

Fever 303 70/73

(95.9%)

34/37

(91.9%)

43/47

(91.5%)

138/146

(94.5%) 0.71

Unexplained

respiratory

illness**

275 48/56

(85.7%)

30/34

(88.2%)

38/47

(80.9%)

99/138

(71.7%) 0.06

Tachypnea 182 9/28 (32.1%) 9/27 (33.3%) 15/37

(40.5%) 41/90 (45.6%) 0.51

Abnormal Breath

Sounds 113 6/21 (28.6%) 5/18 (27.8%) 6/19 (31.6%) 10/55 (18.2%) 0.57

Sore

throat/pharyngitis 169

13/29

(44.8%)

14/28

(50.0%)

19/34

(55.9%) 28/78 (35.9%) 0.22

Cyanosis 99 2/19 (10.5%) 1/15 (6.7%) 1/18 (5.6%) 3/47 (6.4%) 0.93

Excessive Sputum

Production 132 2/20 (10.0%) 3/22 (13.6%) 2/27 (7.4%) 15/63 (23.8%) 0.19

Rhinorrhea 173 24/45

(53.3%)c,d 6/24 (25.0%) 5/31 (16.1%)a 8/73 (11.0%)a <0.01

Diarrhea 180 7/30 (23.3%) 5/26 (19.2%) 8/33 (24.2%) 20/91 (22.0%) 0.97

Abdominal Pain 136 5/26 (19.2%) 5/19 (26.3%) 8/21 (38.1%) 13/70 (18.6%) 0.28



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Vomiting 158 9/30 (30.0%) 7/22 (31.8%) 8/26 (30.8%) 11/80 (13.8%) 0.08

Headache 151 5/27 (18.5%)c 4/17

(23.5%)c

18/26

(69.2%)a,b,d

28/81

(34.6%)c <0.01

Fatigue or Malaise 121 4/21 (19.1%) 4/15 (26.7%) 7/24 (29.2%) 21/61 (34.4%) 0.60

Myalgia 135 2/23 (8.7%)d 6/21 (28.6%) 4/23 (17.4%) 28/68

(41.2%)a 0.01

Neurologic

Involvement 106 1/21 (4.8%) 2/18 (11.1%) 0/16 (0%) 3/51 (5.9%) 0.57

Psychiatric 91 0/19 (0%) 2/14 (14.3%) 1/14 (7.1%) 4/44 (9.1%) 0.46

Bleeding gums

and/or nose 133 0/23 (0%) 2/23 (8.7%) 3/25 (12.0%)d 0/62 (0.0%)c 0.02

Enlarged liver 93 0/18 (0%) 1/15 (6.7%) 1/16 (6.3%) 1/44 (2.3%) 0.62

Conjunctivitis 134 1/23 (4.4%) 1/22 (4.6%) 0/23 (0%) 1/66 (1.5%) 0.64

*Overall p‐value. Comparisons between age groups are considered significant at p<0.01, reduction in

alpha level is due to application of a Bonferroni correction for multiple comparisons.

** Unexplained respiratory illness is defined as including cough, shortness of breath or difficulty

breathing.

a Significantly different from age 0‐5, b Significantly different from 6‐11, c Significantly different from 12‐

17, d Significantly different from ≥18



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Table 4. Survival by Median Laboratory Values within 24 hours of Hospital

Admission

Pediatric Cases (Age <18 years)

Laboratory Parameter N Fatal Cases Non Fatal Cases p‐value

Leukocyte Count – median

count, per mm3 61 2800 (400‐18,300) 5100 (2000‐15,900) <0.01

Lymphocyte Count– median

count, per mm3 21 800 (250‐1700) 2028 (1040‐4256) <0.01

Platelet Count –

median count, per mm3 52

123,000 (35,000‐

314,000)

188,000 (122,500‐

528,000) <0.01

Creatine Kinase – median

count , U/liter 9 1430 (52‐3429) 297 (82‐1396) 0.54

Alanine aminotransferase –

median, U/liter 31 60 (8‐8750) 22 (11‐299) 0.03

Aspartate aminotransferase—

median, U/liter 31 263 (20‐3230) 53 (16‐107) <0.01

Lactate dehydrogenase –

median, U/liter 11 1606 (604‐4032) 1518 (420‐4478) 0.93

Creatinine –

median, μmol/liter 22 0.70 (0.16‐1.04) 0.38 (0.20‐0.53) 0.02

Urea nitrogen –

median, mg/dL 16 21 (10‐58) 15 (7‐22) 0.19

Hemoglobin 47 13 (10‐37) 11 (10‐14) 0.04

Hematocrit 35 37 (4‐51) 33 (27‐38) 0.01



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Table 5. Relative Risk of Death by Symptoms on Presentation for Medical Care

and Age Group

Age in years

Symptom N 0‐5 6‐11 12‐17 >18

Fever 303 0.81 (0.16, 4.22) 0.88 (0.38, 2.06) 1.72 (0.64, 4.62) 0.95 (0.63, 1.43)

Unexplained

respiratory illness with

cough, shortness of

breath or difficulty

breathing

275 0.47 (0.27, 0.82) 2.80 (0.50, 15.53) 0.84 (0.73, 0.97) 0.87 (0.72, 1.06)

Tachypnea 182 0.53 (0.20, 1.41) 1.56 (0.87, 2.78) 1.29 (1.03, 1.62) 0.92 (0.73, 1.16)

Abnormal Breath

Sounds 113 0.83 (0.34, 2.05) 1.73 (0.83, 3.61) 1.18 (0.94, 1.49) 1.16 (0.80, 1.68)

Sore

throat/pharyngitis 169 0.49 (0.20, 1.21) 1.25 (0.71, 2.19) 0.68 (0.47, 0.98) 0.89 (0.66, 1.20)

Excessive Sputum

Production 132 0.82 (0.20, 3.43) 1.06 (0.44, 2.52) 1.14 (0.98, 1.31) 0.80 (0.51, 1.25)

Rhinorrhea 173 0.13 (0.03, 0.53) 0.75 (0.32, 1.78) 0.68 (0.33, 1.41) 0.49 (0.20, 1.20)

Diarrhea 180 0.88 (0.43, 1.78) 0.60 (0.20, 1.83) 1.20 (1.00, 1.41) 1.25 (1.02, 1.54)

Abdominal Pain 136 1.29 (0.74, 2.24) 1.05 (0.45, 2.45) 1.14 (0.77, 1.69) 1.22 (0.99, 1.52)

Vomiting 158 0.67 (0.30, 1.47) 1.19 (0.64, 2.22) 1.05 (0.75, 1.47) 1.09 (0.80, 1.48)

Headache 151 0.68 (0.22, 2.09) 0.72 (0.25, 2.05) 0.89 (0.62, 1.27) 1.15 (0.90, 1.46)

Fatigue or Malaise 121 0.43 (0.07, 2.43) 0.46 (0.08, 2.72) 0.81 (0.49, 1.33) 0.98 (0.76, 1.26)



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Myalgia 135 NA 0.50 (0.15, 1.64) 0.59 (0.22, 1.61) 0.80 (0.59, 1.10)



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Table 6: Rhinorrhea and Odds Ratios for Death among Children: Two Models

N Unadjusted OR N Adjusted OR p‐value

All cases with information on rhinorrhea

(Model 1)

Rhinorrhea noted at presentation for

medical care (yes/no)

100 0.11 (0.04, 0.28) 100 0.24 (0.08, 0.77) 0.02

Oseltamivir treatment (yes/no) 100 0.94 (0.43, 2.09) 100 1.41 (0.50, 3.96) 0.51

Age (years) 100 100

0‐5 0.10 (0.03, 0.30) 0.15 (0.04, 0.52) <0.01

6‐11 0.32 (0.09, 1.14) 0.32 (0.08, 1.24) 0.10

12‐17 Ref Ref

Egypt (vs. all other countries) 100 0.04 (0.01, 0.35) 100 0.16 (0.02, 1.78) 0.14

Oseltamivir treated cases with

information on rhinorrhea (Model 2)

Rhinorrhea at presentation for medical

care

56 0.15 (0.04, 0.52) 44 0.38 (0.03, 5.55) 0.48

Days from symptom onset to oseltamivir

treatment (delay in starting treatment)

44 1.85 (1.30, 2.64) 44 1.75 (1.17, 2.61) 0.01

Age (years) 56 1.21 (1.05, 1.38) 44 1.38 (1.02, 1.85) 0.04



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