Download Appendix A: Calculations of transition rates in the outcome tree

SUPPLEMENTARY MATERIAL
Detailed information in the outcome trees
Q fever
Acute illness
The Q fever acute illness is similar to the acute illness of influenza A(H1N1) pdm09, which is
used as a proxy for Q fever acute illness, but is different in two aspects. First, those under 15
years of age are far less frequently symptomatic (12.5%) than cases that are over 15 years of age
(40%) [1]. Secondly, the acute illness of Q fever has a higher percentage of pneumonia (61.5%
[2]) than influenza A(H1N1) pdm09 (34.3% of hospitalized cases which are 2.2% of infected
[3]) and hospitalization is also higher for Q fever (19.5%) [2] than A(H1N1) pdm09 (2.2%) [3].
Therefore the health outcome acute illness was divided into two health states, taking the
difference in pneumonia (61.5% - (34.3%x2.2%) = 60.7%) to be a severe state and the remaining
as mild heath state (1-60.7%=39.3%). The severe health state disability weight used was “P
pneumonia – 2 weeks in the year” and the mild health state disability weight used was "P
influenza – 2 weeks in the year" [4]. The result was age specific transition rate with mild and
severe health states. Under 15 years of age had a lower symptomatic transition rate (12.5% [1])
and have typically a milder acute illness so only "P influenza – 2 weeks in the year" disability
weight was used. Above 15 years of age the symptomatic transition parameter totaled the
average from literature (40% of infected [5]) but divided into the two health states mild (39.3%
of symptomatic (40% of infected)=15.7%) and severe (60.7% of symptomatic cases (40% of
infected)=24.3%). The disability weights proxies used for mild (influenza) and severe
(pneumonia) better represented the greater severity of the acute illness of Q fever versus
influenza. The number of asymptomatic cases is equal to the number of infected minus the
number of infected cases.
Acute illness mortality is quantified by two studies of the Netherlands outbreak. One
study on hospital mortality there were 9 patients of the 749 known hospitalizations that died [6]
and knowing that roughly 20% of symptomatic patients are hospitalized [7], we can use 0.24%.
A second parameter value comes from the number of deaths in 2009 as a total of the number of
notified cases, 6 in 2357 notified cases, 0.25% [7]. Both were used in the model as a uniform
distribution.
Chronic Q fever
The transition rate of symptomatic cases developing chronic Q fever (1.6%) [8] is derived
from the Netherlands outbreak data and assumed to be the same for asymptomatic cases. This
assumption is based upon contact with medical staff from the Jeroen Bosch Hospital, 'sHertogenbosch, the Netherlands who observed a limited number of chronic cases developing
from asymptomatic infections and from the identification of an asymptomatic cases from the
outbreak in Switzerland in 1983 developing chronic Q fever. The average duration of chronic Q
fever before developing symptoms (2.75 years) [9] is included in the model as it reduces the life
expectancy of the later health outcomes endocarditis and vascular infection.
Post-infectious fatigue syndrome
Fatigue is difficult to quantify and is a subjective outcome. Follow up studies after large
outbreaks provide some information regarding duration and proportion retaining fatigue. One
large outbreak cohort that is being followed from the United Kingdom used standard clinical
criteria to quantify proportion of fatigue after 5 years [9] and after 10 years [10]. The first follow
up reported a larger proportion of idiopathic chronic fatigue (ICF) in Q fever cases (42.3%)
compared to matched controls (26%), a difference of 16.3%. At the ten year follow up point they
matched cases on the presence of comorbidities and attending the hospital but still the Q fever
cases had a higher proportion of ICF (21.6%) compared to controls (5.4%), a difference of
16.2%. The same study also looked at matched cases with comorbidities and/or attending a
hospital but that had an even larger difference (71.4%) compared to controls (28.6%) and may
overestimate the severity by incorporating comorbidity.
Recent literature from the Netherlands outbreak on the proportion fatigue after 12 to 26
months is even higher (58.9% versus 12.3% in controls) than after five or ten years of follow up
[11]. Interpreting severity of patients developing fatigue, two health states were used with similar
disability weights but different durations. The mild health state (46.6%) is clinical cases that
recover within 12 to 26 months and a severe health state (16.2%-16.3%) that are assumed to
recover after 10 years. To prevent double counting the severe cases are removed from the mild
health state (46.6% - mild health state).
For post infectious fatigue syndrome, the health outcome "Major depression, mild
episode" [4] was used as a proxy though it is likely to be an under-estimation given that the
mode EQ-5D and mean EQ-5D for 85 patients with chronic fatigue syndrome is larger than the
health outcome "Major depression, mild episode" [12].
Endocarditis
The proportion of chronic Q fever cases that develop endocarditis from the literature
gives us three values for a PERT distribution, a minimum (60%) [5], a maximum (75%) [13] and
a most likely (73%) [14] value. A large proportion of endocarditis cases develop heart failure
(67%) [5], so the proxy disability is taken from the WHO GBD, “congestive heart failure" [15].
The duration is reported to be less than one year (0.583) [16]. In the Netherlands we assumed
that all cases would be treated and reduce the overall mortality (8%) [5] from the untreated
proportion (100%) [14].
Vascular infection
The proportion of chronic Q fever cases that develop vascular infection is not as common
in most outbreaks. The available literature is limited and a single estimate was found (8%) [14].
For the remaining information estimates were taken from endocarditis health outcome including
duration, disability and mortality.
Influenza
Acute illness
The acute illness is assumed to be all infected cases in the model and asymptomatic cases
are not included as they do not contribute to the total burden because they do not develop any
long term sequelae. The disability weight is taken from the Stouthard et al., “Influenza burden
per year” and represents the average, at population level, severity of a seasonal influenza
infection (0.01 per year) [4]. This includes all complications of the acute illness and different
severities. This includes, but is not limited to, acute respiratory distress syndrome (ARDS),
sepsis and otitis media. It does not include permanent disabilities from these health states though,
which need to be added. The mortality for influenza A(H1N1) pdm09 scenario 1 is taken from
estimates by Wijngaard et al. that modeled mortality of A(H1N1) pdm09 [17].
Permanent disability due to acute respiratory distress syndrome (ARDS)
After an acute infection a small percentage (0.038%) retain disability as a direct result of
ARDS for the remainder of their life expectancy. To derive this proportion that develops
permanent disability from ARDS the proportion of ARDS cases (63 of 1841 (3.4%) of
hospitalized cases (2% of symptomatic cases) = 0.068%) [3], are multiplied by the proportion
that retain permanent symptoms (56%) [18]. The disability weight proxy used is from Stouthard
et al. “COPD” (0.17) [4].
Permanent disability due to otitis media (OM)
After an acute influenza infection a small percentage (0.00000698%-0.0000088%) retain
permanent disability due to otitis media (=deafness), for the remainder of their life expectancy.
To derive this proportion that develops deafness, the proportion of cases developing otitis media
(0.65%) [19] of cases attending a GP (17.9%-22.6% of symptomatic) [20] is multiplied by the
proportion that retain permanent symptoms (0.006%) [15].
Permanent disability due to sepsis
After an acute influenza infection a percent of the cases (0.026%) retain permanent
disability after developing sepsis for the remainder of their life expectancy. To derive this
proportion the proportion of hospitalized cases developing sepsis (1.58% (29/1841) of
hospitalized (2% of symptomatic)) [3] is multiplied by the proportion retaining permanent
disability (82%) [21]. The disability used is for sepsis long term sequelae (0.28) [21].
Sensitivity Analysis
A sensitivity analysis was performed and estimates were obtained for the change relative to the
total DALY estimate from baseline scenario for both diseases. The table shows lower bound
estimates for a disability weight set to zero, and upper bound estimates for a disability weight set
to 1, leaving all other parameters unchanged. In parentheses results are presented as percentages
of the baseline estimates. For influenza the acute illness disability weight had the largest
influence on the total DALY estimates. The disability weight for ARDS and sepsis contributed
much less and long term sequelae due to otitis media contributed less than 1 DALY.
For Q fever the post infectious fatigue syndrome severity changed the estimate the most followed
by the severity of the acute illness health outcome. The two health outcomes for chronic Q fever
(endocarditis and vascularitis) changed the DALY estimate by less than one percent in either
direction.
Supplementary Table S1 Sensitivity analysis of disability weights showing range of health state.
Weight = 0
Weight = 1
20389 (83%)
23003 (94%)
24484 (100%)
22932 (94%)
429904 (1755%%)
31230 (128%)
24485 (100%)
28477 (116%)
A(H1N1) pdm09
Acute influenza
ARDS† long term disability
Otitis media long term disability
Sepsis long term disability
Q fever
Acute Q fever - mild
5751 (99%)
Acute Q fever - severe
5089 (88%)
Endocarditis
5752 (99%)
Vascularitis
5793 (99%)
PIFS* - mild
5118 (88%)
PIFS* - severe
3145 (54%)
*Post infectious fatigue syndrome
†Acute respiratory distress syndrome
10333 (178%)
12166 (210%)
5958 (103%)
5815 (100%)
9970 (172%)
22088 (381%)
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