Chapter 33 1

Invasive Pneumococcal Bacteremia in a 9-Year-Old 2

Boy Caused by Serotype 1: Course, Treatment 3

and Costs 4

Teresa Jackowska, Joanna Zaleska-Ponganis, Magdalena Szkilladz-Skiba, 5

and Dominik Dziurda 6

Abstract  Streptococcus pneumoniae is a leading cause of bacteremia, sepsis, meningitis, pneumonia, 7

sinusitis, and acute otitis media in young children. Some serotypes are associated with particular disease 8
syndromes, such as complicated pneumonias in children, or with higher rates of hospitalization in 9
children and are consistently responsible for outbreaks in certain populations. In this report we 10
describe a case of a nine-year-old boy who developed an abscess of pleura and invasive pneumococcal 11
bacteremia. The boy was admitted to the hospital with abdominal pain and vomiting, accompanied by 12
mild cough and fever. Chest X-ray revealed lower left lobe consolidation with pleural inflammation 13
and chest CT showed extensive interstitial-alveolar changes in the left lung with atelectasis and pleural 14
effusion causing a reduction in lung volume up to the fourth rib. From the 6th day of hospitalization 15
on, suction drainage and intrapleural administration of alteplase were continued for 5 days. Intravenous 16
antibiotics were administered for subsequent 32 days. The course of disease was complicated with 17
labial herpes and acute adenoviral gastroenteritis. The costs of diagnosis (11.7%), pharmacotherapy 18
(55.2%), hospitalization (30.7%) and additional procedures (2.4%) were about €4,444, while the cost 19
of treatment from the perspective of the National Health Fund was only €1,508. The costs of treating 20
the boy with sepsis caused by S. pneumoniae serotype 1 were thus about three times higher than those 21
from the perspective of providers of the National Health Fund. Administration of a new pneumococ- 22
cal conjugated vaccine containing serotype 1 (PHiD-CV10 or PCV13) could have prevented invasive 23
pneumococcal disease in the described patient. 24

Keywords  Bacteremia • Invasive pneumococcal disease • Serotype 1 • Empyema • Pneumococcal 25

vaccine • Treatment cost 26

T. Jackowska (*) • J. Zaleska-Ponganis • M. Szkilladz-Skiba

Department of Pediatrics, Medical Center for Postgraduate Education,
Marymoncka 99/103 St, 01-813 Warsaw, Poland
Department of Pediatrics, Bielanski Hospital, Warsaw, Poland
e-mail: tjackowska@cmkp.edu.pl
D. Dziurda
Department of Health Technology Assessment, GSK Services, Warsaw, Poland

M. Pokorski (ed.), Respiratory Regulation - Clinical Advances,

Advances in Experimental Medicine and Biology 755, DOI 10.1007/978-94-007-4546-9_33,
© Springer Science+Business Media Dordrecht 2012
 T. Jackowska et al.

27 33.1 Introduction

28 Streptococcus pneumoniae (S. pneumoniae) is still a major cause of serious invasive infections, such
29 as septicemia, meningitis, and bacteraemic pneumonia, associated with high morbidity and mortality,
30 especially among very young children. S. pneumoniae is also a leading cause of non-invasive pneumonia,
31 sinusitis, and acute otitis media (Centers for Disease Control and Prevention 2000). S. pneumoniae is
32 much more likely to be associated with nasopharyngeal colonisation than to cause invasive disease
33 (Sulikowska et al. 2004).
34 The bacterial species S. pneumoniae consists of 90 immunologically distinct serotypes. Some
35 serotypes seem to be of disproportionate importance as causes of disease in very young infants, in
36 older children, in immunocompromised individuals, or in elderly people. Some serotypes seem to be
37 associated with particular disease syndromes, such as complicated pneumonias in children, or with
38 higher rates of hospitalization in children or mortality in adults, and are consistently responsible for
39 outbreaks in certain populations (Hausdorff et al. 2000).
40 Invasive pneumococcal disease (IPD) is defined as the recovery of an isolate of S. pneumonia from
41 a normally sterile site, such as blood, cerebrospinal fluid (CSF), pleural fluid, joint aspirate, pericardial
42 fluid, or peritoneal fluid. Among all bacteremic infections in hospitalized patients, S. pneumoniae
43 etiology constitutes 4–12% cases (Centers for Disease Control and Prevention 2000). The highest
44 incidence of pneumococcal disease occurs in children under the age of 5. Pneumonia, especially
45 pneumococcal pneumonia, is considered one of the major causes of childhood mortality (Williams
46 et  al. 2002). In Poland, the incidence rate of IPD is low in all age groups, even when IPD cases
47 identified by polymerase chain reaction (PCR) are included. PCR-based assessments constituted only
48 7.1% and 6.2% of all IPD cases in 2008 and 2009, respectively. The general IPD incidence rate in
49 Polish children under the age of 5 in 2009 was 2.85/100,000. In children under the age of 5, the most
50 frequently reported isolates belonged to serotypes 14, 6B, and 19 F (52.7% of cases of IPD), and
51 among children 5–14 years old was dominated by serotype 1 (26.8%) (Skoczynska et al. 2011).
52 Poland is among the countries without mass vaccination against pneumococcal diseases. However,
53 anti-pneumococcal conjugated vaccines are registered and highly recommended. For some risk
54 groups, the vaccine has been free of charge since 2008 (Annex to the Communication from the Chief
55 Sanitary Inspector of 22 October 2009). It is estimated that about 30% of children have a voluntary
56 (non-refundable) vaccination against pneumococcal (PCV7 or currently PCV13 by Pfizer, and PCV10
57 by GlaxoSmithKline) (Jackowska and Kłyszewska 2010). The objective of this report was to present
58 a case of invasive pneumococcal disease including the costs of therapy.

59 33.2 Methods

60 This report describes data collected in accordance with the Declaration of Helsinki for Human
61 Experimentation and it was approved by a local Ethics Committee.

62 33.2.1 Case Report

63 We describe the case of a 9-year-old boy who suffered from pneumonia and subsequently developed
64 a pleural empyema and invasive pneumococcal bacteremia. The boy was admitted to the hospital by
65 a surgeon, because of an episode of abdominal pain and vomiting accompanied by a mild cough and
33  Invasive Pneumococcal Bacteremia in a 9-Year-Old Boy Caused by Serotype 1…

fever. Before admission, the boy was healthy, with occasional respiratory tract infections. He had been 66
vaccinated against tuberculosis, diphtheria, tetanus, pertussis, polio virus, hepatitis B, and measles. 67
Vaccinations against Haemophilus influenzae, Neisseria meningitidis and Streptococcus pneumoniae 68
were not performed. 69
The general condition was serious; the patient was dehydrated, in a sitting position (respiratory rate 70
46/min, pulse 110 bpm, temperature 39.6°C, SaO2 90%). Laboratory studies found very high rates of 71
inflammation (C reactive protein; CRP – 386.4 mg/L, erythrocyte sedimentation rate, ESR – 140 mm/h, 72
leukocytosis – 30.1 G/L with rejuvenation and a shift to the left – granulocytes clubbed 13, segmented 73
79), features of hypercoagulability (elevated D-dimer – 2,223 ng/mL and fibrinogen – 496 mg/dL), 74
and the presence of fibrin breakdown products (FBP). Laboratory tests during the disease are shown 75
in Table 33.1. On the lung auscultation, there was dullness below the third rib, and a reduction in the 76
respiratory murmur over the left lung. Abdomen palpation was difficult because of the intensified pain 77
and the patient’s defence reaction. A chest X-ray revealed lower left lobe consolidation with symptoms 78
of pleural inflammation. 79

33.2.2 Course of Disease 80

After taking a blood culture, antibiotic treatment with cefuroxime and netilmicin was administered. 81
The patient’s condition was worsening and we decided to administer intravenous immunoglobulin on 82
the third and fifth day of treatment. On the fourth day, after isolating the S. pneumoniae from the blood 83
culture (sensitive to penicillin, erythromicin, clindamycin, ampicillin, amoxicillin/clavulanic acid, 84
trimetoprim/sulphamethoxazole, and vancomycin) benzylpenicillin was added to the therapy, but 85
netilmicin was stopped after 2 days. 86
The National Reference Center for Bacterial Meningitis in Warsaw, Poland found that the cause 87
was serotype 1 IPD S. pneumoniae. Five days after admission, a chest X-ray was performed because 88
of increasing dyspnea (respiratory rate 60/min, pulse 115 bpm, temperature 38.2°C, SaO2 90%). 89
It revealed significant progression of the inflammatory process in the left lung and pleural effusion. 90
A chest computer tomography (CT) showed extensive interstitial-alveolar changes in the left lung, 91
with atelectasis and pleural effusion causing a reduction in the lung volume up to the fourth rib 92
(Fig. 33.1a). 93
From the 6th day of hospitalization, pleural suction drainage and intrapleural administration of 94
alteplase, a tissue-type plasminogen activator (Actilise; Boehringer Ingelheim), were instituted and 95
continued for the next 5 days. The patient received 15 alteplase doses in all (three times 10 mg/daily). 96
At the time of pleural drainage, approximately 1,000 ml of purulent liquid was obtained. Intravenous 97
antibiotics were administered for 32 days in total. Benzylpenicillin (15 days) followed by cefotaxime 98
and clindamycin (both for 14 days). A control chest CT, made on the 20th day of treatment, revealed 99
that the fluid in the left pleural cavity had disappeared (Fig. 33.1b). During the whole hospitalization 100
time, physiotherapy was applied. The course of the disease is shown in Fig. 33.2. After 36 days of 101
hospitalisation, the boy was discharged home in a good general condition. The course of the disease 102
was complicated by labial herpes and acute adenoviral gastroenteritis, despite simultaneous treatment 103
with aciclovir since the first day of treatment. 104
The following final diagnosis was established for this case: 105

1. Invasive pneumococcal disease (Streptococcus pneumoniae serotype 1) presenting as lobal pneu- 106
monia complicated by pleural empyema and bacteremia. 107
2. Labial herpes. 108
3. Acute adenoviral gastroenteritis. 109
t1.1 Table 33.1  Laboratory results in the consecutive days of treatment
t1.2 Days of treatment 1 6 11 13 16 18 23 31
t1.3 ESR mm/h (<12)a 140 60 155 125 130 – 85 75
t1.4 CRP mg/L (0.1–5.0)a 386 172 75 – 7.8 – 2.3 –
t1.5 WBC × 103/mL 30.1 22.9 16.9 8.8 6.6 7.4 7.0 8.4
t1.6 (3.5–10.0)a
t1.7 Blood smear Band 13, Segmented 84 Meta–myelocyte 1, Segmented 54 Segmented 52 Segmented 52 Band 3, Segmented 55
t1.8 (only neutrophils) segmented 79 band 2, segmented 46
t1.9 segmented 74
t1.10 Hbg/dL (11.0–16.5)a 12.6 11.1 10.1 10.4 10.9 11.1 12.1 11.2
t1.11 Ht % (35.0–50.0)a 36.2 31.6 30.4 30.3 33.2 32.1 36.6 34.4
t1.12 PLT × (103/mL) 636 897 1,319 1,191 1,167 665 528 507
t1.13 (150–390)a
t1.14 Fibrinogen (mg/dL) 496 447 378 – – – – 382
t1.15 (169–392)a
t1.16 D-dimers ng/mL 2,223 4,333 760 – – – – 548
t1.17 (<500)a
t1.18 FBP (negative)a Positive Negative Negative – – – – Negative
a
t1.19 Norm range
T. Jackowska et al.
33  Invasive Pneumococcal Bacteremia in a 9-Year-Old Boy Caused by Serotype 1…

Fig. 33.1  Chest CT; (a) Extensive interstitial-alveolar changes in the left lung with atelectasis and pleural effusion
(Day 5); (b) Resolution of changes after 20 days of treatment

Fig. 33.2  Disease course

33.2.3 Economic Analysis 110

An in-depth search of literature was conducted to gain a European perspective of resource utilization 111
linked with inpatient treatment of complicated invasive pneumonia. Available costs data were inflated 112
to 2010 costs using the Consumer Price Index (OECD 2011a) and standardized using the exchange 113
rate to Euro (European Central Bank 2011) and purchasing power parities (PPP) for health (OECD 114
2011b) (Table 33.2). 115
The nominal average treatment cost for patients with invasive pneumonia differs among countries 116
being in a range of €2,346–8,052. The level of refunding offered to hospitals in the Polish National 117
Health Fund (NHF) (€1,508) is up to three times lower than that in Belgium, Germany, or Sweden. 118
Nevertheless, NHF reimbursement properly reflects differences in PPP between Poland and other 119
countries. A significant disproportion between the real costs of the described case and the diagnosis- 120
related group (DRG) classification value might be due to a high proportion of spending related to 121
 T. Jackowska et al.

t2.1 Table 33.2  Costs of treatment of complicated invasive pneumonia depending on country
t2.2 Country (Currency/Year)a Definition Cost (€2,010) Cost (PPP €2,008)
t2.3 Norway (NOK/2004) (Wisloff et al. 2006) Consolidated Pneumonia 5,856 3,485 [AU1]
t2.4 Sweden (SEK/2006) (Bergman et al. 2008) Pneumonia (hospitalized) 3,402 2,652
t2.5 Pneumonia (hospitalized) 6,702 5,225
t2.6 with empyema
t2.7 Finland (€/2004) (Salo et al. 2005) Pneumonia, inpatient care 2,346 1,988
t2.8 Belgium (€/2006) (Beutels et al. 2006) Hospitalised pneumonia 5,830 4,519
t2.9 Netherlands (€/2009) (Rozenbaum Invasive pneumoniab 5,142 4,897
t2.10 et al. 2010)
t2.11 Germany (€/2005) (Claes et al. 2009) Inpatient pneumonia 5,388 5,231
t2.12 Italy (€/2004) (Marchetti Inpatient pneumonia 2,557 2,243
t2.13 and Colombo 2005) Other pneumococcal IPDc 4,278 3,753
t2.14 Switzerland (CHF/2000) (Ess et al. 2003) Complicated pneumonia 3,592 2,243
t2.15 England (£/2002) (McIntosh et al. 2003) Inpatient pneumoniad 3,691 3,858
t2.16 Pneumonia with empyema 8,052 8,417
t2.17 Poland (PLN/2009) (National Health Invasive pneumonia (DRG NHF) 1,508 3,136
t2.18 Fund 2011) Case Report 4,767 9,909
t2.19 a
€1 = 9,295 SEK 2006 exchange rate (recalculated)
t2.20 b
5–19 age category
t2.21 c
According to description this category better reflect invasive pneumonia
t2.22 d
Average cost of inpatient pneumonia treatment (recalculated)

t3.1 Table 33.3  Summary of treatment costs borne by healthcare provider concerning the patient with Streptococcus [AU2]
t3.2 pneumonia-induced sepsis reported in this study
t3.3 Category Description Number (Unit) Cost (€) Cost (€) (% of overall cost)
t3.4 Hospital Stay Days in ward 32 days – 1,365 (30.7%)
t3.5 Diagnostic tests Diagnostic tests 108 (unit) – 519 (11.7%)
t3.6 Imagin tests 18 (unit) –
t3.7 Pharmacotherapy Cefuroxime 54 (g) 40 2,454 (55.2%)
t3.8 Netilmicin 1.68 (g) 56
t3.9 Immunoglobulin IgG 10 (g) 642
t3.10 Penicillin 90 (MIU) 31
t3.11 Alteplase 0.15 (g) 1,544
t3.12 Cexotaxime 46.20 (g) 28
t3.13 Clindamycin 10.85 (g) 567
t3.14 Fluconazole 4.50 (g) 7
t3.15 Aciclovir 11.75 (g) 32
t3.16 Omeprazole 0.19 (g) 4
t3.17 Others n/a 14
t3.18 Additional Surgeon consultation 9 (times) 23 105 (2.4%)
t3.19 procedures Establishing pleural cavity 1 (procedure) 59
t3.20 drainage conditions CBO
t3.21 Intravenous general anesthesia 1 (procedure) 24
t3.22 Overall cost of treatment 4,444 €

122 pharmacotherapy, which is not susceptible to differences in PPP (a similar nominal level among
123 ­countries) and low valuation of an additional day of hospital stay in the Polish health care system.
124 The costs of operations and the cost to providers, resulting from the treatment performed and reim-
125 bursement from the National Health Fund are presented in Table 33.3. The costs of hospitalization
126 (30.7%), diagnosis (11.7%), pharmacotherapy (55.2%), and additional procedures (2.4%) were about
33  Invasive Pneumococcal Bacteremia in a 9-Year-Old Boy Caused by Serotype 1…

€4,444, whereas the cost of treatment from the perspective of the National Health Fund was only 127
€1,508. The breakdown of costs incurred by the hospital to refund the cost of treatment by the NHF 128
leads to the conclusion that the refunding of therapy costs from the public means is far insufficient to 129
cover the real costs of treating a patient with sepsis caused by S. pneumoniae. 130

33.3 Discussion 131

Invasive pneumococcal disease, caused by S. pneumoniae, remains a leading cause of serious illness 132
in children and adults worldwide (Centers for Disease Control and Prevention 2000). In February 133
2000, the heptavalent pneumococcal vaccine (Prevenar; Wyeth) was licensed for use in the United 134
States for the prevention of invasive pneumococcal disease in children under the age of 5. A total of 135
four doses of PCV7 at the ages of 2, 4, 6, and 12–15 months were subsequently recommended for 136
routine administration in young children by the American Academy of Pediatrics in August 2002 and 137
the Advisory Committee on Immunization Practices (ACIP) in October 2000 (American Academy of 138
Pediatrics 2000). The vaccine was recommended for all children from 2 to 23 months of age, and for 139
children 24–59 months of age who are at increased risk of pneumococcal disease (Advisory Committee 140
on Immunisation Practices 2000). From April 2008, by the decision of ACIP, one dose of PCV7 141
should be administered to all healthy children aged 24–59  months who have not completed any 142
recommended schedule for PCV7 (CDC 2008). Two new inoculations were registered, in April 2009, 143
PCV10 (GlaxoSmithKline), and in February 2010 PCV13 (Pfizer), including three (1, 5, 7 F) and six 144
(1, 3, 5, 6A, 7 F, and 19A) new serotypes, respectively. Serotype 1 and 5 diseases (serotypes not 145
represented in PCV 7) are important types in older children in industrialised countries and rarely 146
cause mild bacteremias (Hausdorff 2007). 147
Prognosis of the severity, the incidence of complications, or death from pneumococcal infections 148
is related to the clinical course of the infection, the patient’s clinical characteristics, and the type of 149
invasive pathogens (S. pneumoniae serotype and degree of susceptibility). The serotype distribution 150
of IPD cases is highly dependent on age. Some serotypes affect only the youngest, while some have a 151
very broad age spectrum. IPD often occurs in children up to 2 years of age, but may also appear in 152
children older than 5. In Poland, pneumococci of serotype 1 were more prevalent in the group of 153
5–14  years old than in all other age groups (26.8% of all infections caused by pneumococci of 154
serotype 1 occurred among these patients; p < 0.001) and were responsible more often for bacteremia/ 155
sepsis and invasive pneumonia (respectively 15.2% and 13.9% of these infections were due to sero- 156
type 1) than for meningitis (1.9% of infections; p < 0.001) (Skoczynska et al. 2011). 157
The case presented in the present report indicates that extremely severe pneumococcal infection 158
may be observed, although caused by a serotype associated with less severe course of the disease 159
(serotyp 1). The therapy of severe pneumonia complicated with pleural empyema (besides targeted 160
antibiotic therapy) may be supplemented with the early intrapleural administration of alteplase, which 161
enhanced the efficacy of suction drainage and saves the patient from invasive surgical intervention 162
(Hamblin and Furmanek 2010). At least 40% of all patients with pneumonia will have an associated 163
pleural effusion, although a minority will require an intervention for a complicated parapneumonic 164
effusion or empyema. All patients require medical management with antibiotics. The use of fibrinolytics 165
remains controversial, although evidence suggests a role for the early use in complicated, loculated 166
parapneumonic effusions and empyema (Koegelenberg et al. 2008). However, in our case introduction 167
of alteplase into the treatment regimen (from 7  days) proved to be an efficient intervention, also 168
recommended by other authors as a standard practice for the drainage of complicated parapneumonic 169
effusions (Hawkins et al. 2004). 170
Serotype 1 is considered to be associated with a better prognosis compared with serotypes 5, 7 F, 171
and 3. The serotypes associated with the highest mortality are 7 F (14.8%), 23 F (8.3%), and 3 (8.3%). 172
 T. Jackowska et al.

173 Infection with serotype 7 F is associated with 4.3 times a greater chance of death and 4 times a greater
174 chance of severe infection compared with other serotypes (Ruckinger et  al. 2009). In Poland, in
175 children with severe invasive disease, meningitis, complications, and deaths were noted in the case of
176 infections with serotypes 14, 4, 6B, 19 F, and 23 F (Skoczynska et al. 2011).
177 In the presented case, the prognosis proved successful thanks to intensive therapy (intravenous
178 immunoglobulins, tissue activator plaminogemu, targeted antibiotic therapy, and the use of intensive
179 rehabilitation). However, 35  days of hospitalization with a 7-day pleural drainage was certainly a
180 stressful ordeal. After receiving information that the cause of the disease was vaccinable serotype
181 S. Pneumoniae, the parents immediately went for a pneumococcal vaccination with their four-year-old
182 daughter, who received PCV7.
183 The results of Polish epidemiological studies indicate that the 7-valent pneumococcal vaccine
184 currently provides almost 100% protection against severe cases and deaths associated with invasive
185 pneumococcal disease in children (Grzesiowski et al. 2008). However, the additional coverage offered
186 by the vaccine serotypes 10-valentn (Synflorix) or 13-valent (Prevenar-13) represents another step
187 forward in the development of vaccines. One of the priorities of Polish vaccinologists and pediatricians
188 is urgent inclusion of pneumococcal vaccines for the immunization program. The high cost of
189 vaccines is an understandable obstacle to commencing vaccination of the population. In our case,
190 however, the costs of treating a boy with sepsis caused by S. pneumoniae serotype 1 were three times
191 higher than those from the perspective of National Health Fund providers.
192 Administration of a new pneumococcal conjugated vaccine containing serotype 1 (PHiD-CV10 or
193 PCV13) could have prevented IPD in the described patient. Commencing a population vaccination
194 for each of the registered pneumococcal conjugated vaccine (Synflorix, Prevenar 13) would be an
195 essential step in caring for small children.

196 33.4 Conclusions

197 • Invasive pneumococcal disease may appear also in children more than 5 years old.
198 • Therapy of severe pneumonia complicated with pleural empyema (in addition to targeted antibiotic
199 therapy) may be supplemented with early intrapleural administration of alteplase.
200 • Intrapleural administration of alteplase enhanced the efficacy of suction drainage and protected the
201 patient from invasive surgical intervention.
202 • Administration of a new pneumococcal conjugated vaccine containing serotype 1 (PHiD-CV10 or
203 PCV 13) could have prevented invasive pneumococcal disease in the described patient.
204 • The level of refinancing from public funds of the diagnosis and treatment of patients with sepsis
205 caused by S. pneumoniae is highly insufficient to cover the real costs.

206 Acknowledgements  Supported by CMKP grant 501-1-1-19-42/2009.

207 Conflicts of interest: The authors declare no conflicts of interest in relation to this article.

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 Author Queries
Chapter No.: 33 0001538705

Queries Details Required Author’s Response

AU1 Please check if alignment of text in first column of Table 33.2 is appropriate.
AU2 Please provide the significance of bold numbers in Table 33.3., if appropriate.
AU3 Please provide further details in the reference “Annex to the Communication from the
Chief Sanitary Inspector of 22 October 2009 Immunisation Programme for 2010”.