Case series / outcomes of hospitalizations for swine-origin influenza A (H1N1) 2009
Perez-Padilla, 2009
-Case series of the first 18 persons with pneumonia and laboratory-confirmed S-OIV hospitalized at the INER hospital in Mexico. Retrospective chart review, covering March 24 to April 24, 2009.
-Most patients were young to middle-aged and previously healthy.
-8/18 patients had pre-existing medical conditions. Non-type 1 diabetes was found in 3 patients (3/18 = 17%).
-Respiratory distress requiring intubation and mechanical ventilation in 10 patients during the first 24 hours, and in an additional 2 patients.
-Mortality | hospitalization = 7/18 (39%) patients died after a mean of 14 days of illness onset and after mean 9 days LOS.
-Mortality | ventilation = 7/12 (58%).
-Influenza-like illness that progressed during a period of 5 to 7 days, developed into pneumonia, and had findings of ARDS or acute lung injury on admission.
Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team, 2009
-Case series of the first 642 confirmed cases of human infection in the US.
-April 15- May5, 2009
-Fever (94%), cough (92%), and sore throat (66%) most common symptoms. 25% of patients had diarrhea, and 25% had vomiting.
-40% of patients between ages of 10 to 18 years, only 5% aged 51 years or older.
-399 patients with known hospitalization status.
-Hospitalization | case = 36/399 (9%).
-22 hospitalized patients with known comorbidity / outcome status.
-Chronic medical conditions in 9/22 patients (41%). Diabetes not mentioned.
-ICU | hospitalization = 8/22 (36%).
-Ventilation | hospitalization = 4/22 (18%).
-As of May 5th – Death | hospitalization = 2/22, in a 22-month-old child with neonatal myasthenia gravis and in a 33-year-old pregnant woman.
-Pneumonia admissions appear to be primary viral, no mention of secondary bacterial infections.
Louie, 2009
-Case series of first 1088 hospitalized and/or fatal cases of influenza A (H1N1) in California.
-April 23 – August 11, 2009.
-32% were children < 18 years. Median age of all cases – 27 years.
-Overall rate of hospitalization or fatality per 100000 = 2.8 / 100000
- 11.9 / 100000 in infants < 1year.
- 1.5 in patients aged 70 years or older.
- Overall fatality | hospitalization = 118 / 1088 (11%), after median 12 days from symptom onset.
- See Fig. 2. Hospitalization rates highest in <1 age group, but case (hospitalized) fatality proportion increases with age and higher for those 18+. Highest case-fatality proportion in adults aged 50 years or older, lowest in children < 18 years.
-See Molinari et al., 2007 – Highest case fatality rate was approximately 20% among those aged 50-59 years old – difficult to read off rate on log-scale graph – This is a much higher case fatality in younger adults, but lower case fatality in the elderly, compared to seasonal influenza.
-See Molinari et al., 2007 – Hospitalization rates, on the other hand, are much lower than estimates from seasonal influenza.
-See Molinari et al., 2007 – Departure from seasonal bimodal distribution of hospitalization rates by age, with infants having the highest hospitalization rate – however, highest mortality rates occur in those aged >= 50 years, consistent with seasonal influenza.
-Chronic diseases in 741/1088 (68%).
-In 258 adults (20+) with known BMI, 156 (58%) were obese. 67 (26%) were morbidly obese. Some colinearity with other underlying conditions, since 103 of 156 obese cases also had chronic lung disease, cardiac disease, immunosuppression, and diabetes.
-Diabetes enumerated only for obese patients, detected in 31/103 obese patients. The minimum proportion of diabetes is therefore 31/258 = 12%.
-ICU | hospitalization = 340/1088 (31%).
-Ventilation | ICU = 193/297 (65%) of ICU cases with available information.
-Evidence of secondary bacterial infection = 46/1088 (4%).
-Point of reference – the percentage of adults who are morbidly obese in the US is 4.8% (Ogden, Carroll, Curtin, McDowell, Tabk, and Flegal, JAMA 2006).
-More than one third of adult cases reported nausea or vomiting, and one-fifth reported diarrhea.
-Other differences from seasonal influenza
- Age distribution of composite hospitalization or fatality uniform except for infants in this series – median age = 27 years.
- Those aged 60 years or older may have preexisting immunity.
-RF for disease
- Traditional – pregnancy
- Emergent – not previously independently associated with seasonal influenza – obesity and hypertension – however, may be proxy for other underlying conditions.
-In contrast with the perception that pandemic 2009 influenza A (H1N1) infection causes only mild disease, hospitalization and death occurred at all ages, and up to 30% of hospitalized cases were severely ill.
DL comment
-Louie et al., 2009 provide some evidence to support the conclusion that the virulence of swine flu virus is mild, and the mortality rates very low, compared with seasonal influenza.
From Molinari 2007
-Attack rates from literature: minimum and maximum among age/risk bands imputed.
- Working age adults: 6.6% (Range: 2.6% - 15.5%).
- Children under 5 years old: 20.3% (range 7.5%, 25.8%).
- Elderly individuals: 9.0% (Source? Unable to detect.)
-Death | flu infection
- Age 18-49 – P = 0.00009
- Age 50-64 – P = 0.00134
- Age >= 65 – P = 0.01170
-Hospitalization | flu infection
- Age 18-49 – P = 0.0042
- Age 50-64 – P = 0.0193
- Age >= 65 – P = 0.0421
-Death | hospitalization
- Age 18-49 – P = 0.021
- Age 50-64 – P = 0.069
- Age >= 65 – P = 0.278
Vaillant, 2009
-Analysis of available fatality data from numerous countries, until July 16, 2009, compiled by epidemic intelligence team at Institut de Veille Sanitaire. First death occurred in Oaxaca State, Mexico, with symptom onset on April 4, 2009.
-126168 reported cases. Scarce data availability from African Countries. Data available for 574 deaths.
-Mean age was 37 years, most deaths (51%) occurring in 20-49 year-olds.
-Underlying disease, presence or absence, documented for 241/499 cases.
-Underlying disease | fatality = 218/241 (90%). This may be over-estimated since documented absence was required for a case to fit into the complement, as opposed to simple absence of documented disease.
-“Diabetes and obesity were the most frequently identified underlying conditions).
-Obesity in 7, diabetes in 5, obesity and diabetes in 1, and obesity and/or diabetes in 41 (some patients only had aggregate data available) for total 54 / 193 fatal cases (28%).
Kumar, 2009
-Case series of a multicenter cohort of critically ill adult and pediatric Canadian patients (report of the Canadian Critical Care Trials Group H1N1 Collaborative).
-Critically ill defined as admission to ICU or requiring mechanical ventilation, or FIO2 >= 60%, or need for IV inotropic or vasopressor medication.
-Prospective measurement with coordinating center ensuring data quality.
-April 16 to July 13, 2009.
-215 critically ill patients.
-168 with confirmed or probable A(H1N1) infection.
-Mean age in confirmed or probable 32.3 years. 25.6% of cases were aboriginal. A large cluster of cases were obtained from the greater Winnipeg region (52 patients).
-Comorbidities present in 165/168 (98.2%). Major comorbidities present in 51/168 (30.4%).
-Diabetes, type 1 or type 2, present in 35 /168 (20.8%).
-Ventilation | ICU = 136/168 (81%) during the first day of admission, most were ventilated invasively.
-Fatality | ICU = 29/168 (17.3%).
-As of August 22, 2009, 7107 cases of S-OIV H1N1 infection in Canada.
-Hospitalization | case = 1441/7107 (20.3%).
-ICU | case = 278 / 7107 (3.9%).
-ICU | hospitalization = 278/1441 (19.3%)
-Along the continuum of acuity of care, patients became older and were more likely to have one or more underlying medical conditions. Also more likely to be female.
-Severe disease and mortality concentrated among individuals aged 10 to 60, reminiscent of the W-shaped curve seen during the 1918 H1N1 Spanish pandemic. Few patients > 60 years old admitted to ICU.
-Diabetes and obesity, and other major underlying illnesses are collinear with First Nations status.
DL comment
-Kumar et al. calculate a much higher hospitalization | infection rate than expected for seasonal influenza, according to the estimates provided by Molinari et al., which include circulatory events likely to have been missed in this case series.
-This supports a higher severity of influenza for H1N1, but runs contrary to findings from Louie et al. which suggest that hospitalization rates are lower for H1N1 than those expected for seasonal influenza, as determined by Molinari et al.
-A possible source of bias is exposure suspicious bias, where those with severe influenza are more likely to receive diagnostic testing. The Kumar data likely over-estimate the hospitalization rate of infection, but to an unknown extent.
Jain, 2009
-Case series of patients hospitalized for H1N1 from May 1, 2009, to June 9, 2009 in the US. Retrospective chart abstraction, but all methods standardized.
-13217 cases of infection and 1082 hospitalizations reported to US CDC.
-This case series describes first 272 completed chart abstractions.
-Median age = 21 years.
-Chronic medical condition in 198 of 272 patients (73%). 83% in adults.
-Asthma most common. Diabetes not enumerated.
-BMI available for 231 patients.
-Adult obesity in 29/100 (29%), morbid obesity in 26/100 adults (26%).
-ICU | hospitalization = 67/272 (25%).
-Fatality | hospitalization = 19/272 (7%).
-Underlying illness | ICU = 54/67 (67%).
-Ventilation | ICU = 42/67 (63%).
-Underlying illness | fatality = 13/19 (68%).
-Age distribution different from that of seasonal influenza
- Half of hospitalizations involved those under 18 years.
- Only 5% were aged >= 65 years.
- Possible explanations – increased case ascertainment in schools, etc.
-Other differences from seasonal influenza
- GI symptoms reported in 39% of patients.
- For seasonal influenza, 44 to 84% of adults hospitalized with influenza had an underlying condition. The H1N1 proportion fits into the upper range, at 83%.
-Obesity
- A majority of patients (81%) who were obese had an underlying condition associated with an increased risk of influenza-related complications.
- Prevalence of obesity similar among hospitalized adults and general population – but prevalence of morbid obesity much higher than the estimate 5% in the adult US population.
WHO. Comparing deaths from pandemic and seasonal influenza ( WHO, Geneva: 22 December 2009 (Accessed on October 11, 2010).
-Numbers of confirmed H1N1 deaths during the 2009 pandemic are sometimes compared to numbers of estimated seasonal influenza deaths
-Such comparisons are not reliable.
-Seasonal influenza estimates use statistical models to calculate “excess mortality”
- From all causes
- Regardless of confirmed influenza infection
-Laboratory-confirmed deaths
- Doctors often do not suspect H1N1 infection and do not test.
- When testing confirms H1N1 in patients with underlying medical conditions, the deaths may be attributed to the medical condition.
- Some tests for H1N1 infection are not entirely reliable – false-negative results are a frequent problem.
- Comparable estimates of excess mortality are not available.
-H1N1 appears to affect a younger age group – comparisons of numbers of deaths mask the distribution of deaths among individuals.
Donaldson LJ, Rutter PD, Ellis BM, Greaves FE, Mytton OT, Pebody RG, Yardley IE. Mortality from pandemic A/H1N1 2009 influenza in England: public health surveillance study.
-Estimate mortality from pandemic A/H1N1 2009 influenza up to November 8, 2009.
-Deaths
- Prospective reporting by hospitals, with nil reports mandatory.
-Denominator
- Laboratory confirmed cases ascertained.
- Weekly estimation of incident case numbers using two primary care surveillance networks – 20 million patients in England registered with a GP – estimates for consultation rates for ILI – used to scale up laboratory confirmed cases with those in which laboratory confirmation were not sought.
- Assumed that 50% to 80% of symptomatic ILI did not consult with GP – used to scale up H1N1 cases for those not presenting to medical attention.
- Two week lag in death reporting allowed for.
- Estimates scaled up to UK national population by age and sex groups.
-Case fatality rate – deaths per case of H1N1 influenza – range reported in [], reflecting uncertainty in the consultation rate of symptomatic ILI.
- Overall – 26 [11, 66] per 100 000.
- Children aged < 1 – 30 [2, 260] per 100 000.
- Adults aged 45-64 – 65 [21, 200] per 100 000.
- Adults aged >= 65 – 980 [300, 3200] per 100 000.
-Population fatality rate – Highest in children aged 5-14, in adults aged >= 65 years, and in children aged < 1.
-Number of cases – Highest in those aged 5-14, 15-24, and 25-44.
-Proportion of cases with diabetes – 9%, none of whom had diabetes alone.
-Overall case fatality rate of 0.026% (range [0.011, 0.066]) is lower than most estimates – but is based on a different denominator, intended to provide a better estimate of the true incidence of symptomatic cases.
-Highest mortality rate in the elderly, following a J-shaped curve. No evidence of high case fatality additionally occurring among young healthy adults.
-Elderly – lowest incidence rate but highest case fatality rate.
-The first influenza pandemic of the 21st century is considerably less lethal than was feared.
Reed C, Angulo FJ, Swerdlow DL, Lipsitch M, Meltzer MI, Jernigan D, Finelli L. Estimates of the prevalence of pandemic (H1N1) 2009, United States, April-July 2009. Emerging Infect Dis, 15(12): 2009.
-In most jurisdictions, the large number of ILI samples from milder cases led to a redaction of the previous policy of increased laboratory diagnosis by May 12th – focus on hospitalized patients.
-It is clear that many cases of H1N1 were mild – the true number may never be known, due to limitations in surveillance methodology.
-Reed et al. report incidence over the first 4 months of the pandemic in the US, adjusted for multipliers representing (probabilistic credible range reported for overall figures) …
- Medical care seeking – 42-58% among those not hospitalized (assumed to be 100% among those hospitalized)
- 42% - 2007 BRFSS (Where you ill with the flu? Did you visit a doctor?)
- 52-55% - 2009 ILI survey in 10 states (See BRFSS questions)
- 49-58% - Delaware university survey (Online survey assessed health-seeking behaviors – combined with data from the campus health center – during a large H1N1 outbreak)
- 52% - Chicago community survey
- Specimen collection – 19-34% among those not hospitalized, 40-75% among those hospitalized.
- 25% - 2007 BRFSS
- 22-28% - 2009 ILI survey in 10 states
- 19-34% - Delaware university survey
- Specimen submission – 20-30% among those not hospitalized, 50-90% among those hospitalized.
- 26% - Delaware university survey
- Laboratory detection of H1N1 - sensitivity – 90-100%.
- Reporting of confirmed cases to CDC – inclusion in national statistics – 95-100%.
-Multiplier estimates were obtained from prior studies and recent investigations, including field data, unpublished community surveys on ILI and health-seeking behavior, and the BRFSS.
-Multipliers were executed using a probabilistic model.
-The median multiplier of reported to estimated cases was 79 – every reported case may represent 79 total cases, with 90% probability interval of [47, 148].
-The median multiplier of hospitalized cases was 2.7, 90% probability interval [1.9, 4.3].
-Most cases appeared in the 5-24 age group – this group also had the highest incidence rate per 100 000 (2196), followed by the 0-4 age group (1870). Elderly patients accounted for the smallest number of cases, both absolutely, and as a rate (107 / 100 000).
-Hospitalizations – most occurred in the 5-24 age group. The highest hospitalization rate was estimated for the 0-4 age group. Again, the lowest hospitalization numbers and rates were estimated for the elderly stratum, at 1.7/100 000.
-Estimated total number of symptomatic cases through July 2009 – 3.0 million, 90% probability range [1.8, 5.7]
-Estimated hospitalization rate – 0.45%, 90% probability range [0.16, 1.2].
-Ratio of deaths to hospitalizations during this period was 6% - CDC laboratory-confirmed surveillance data.
-Reported cases of laboratory confirmed pandemic (H1N1) 2009 influenza are likely a substantial underestimation of the total number of actual illnesses that occurred in the community during the spring of 2009.
-Assumptions – representativeness of parameter estimates, parameter estimates obtained from studies of ILI, missing those with milder symptomatic illness.
-The total number of pandemic H1N1 2009 cases in the US during April-July 2008 may have been up to 140 times greater than the reported number of laboratory confirmed cases.
CDC. Updated CDC estimates of 2009 H1N1 Influenza cases, hospitalizations and deaths in the Unites States, April 2009 – April 10, 2010 ( CDC, Atlanta, GA: May 14, 2010 (Accessed October 11, 2010).
-Reasons for undercounting influenza deaths every year
- States not required to report individual flu cases or deaths
- Infrequently listed on death certificates of those who die from flu-related complications.
- Many seasonal flu-related deaths occur after initial infection, due to secondary pneumonia or because of aggravation of an existing chronic illness.
- Lack of testing, or lack of timely testing.
- Diagnostic accuracy – some tests only moderately sensitive.
-On-going estimate of H1N1 cases, hospitalizations, and deaths using the corrections for under-ascertainment employed by Reed et al..
-Reed et al. did not model the reporting of deaths explicitly – rather, the same factors affecting hospitalization are assumed to affect death reporting, and deaths are estimated based on the proportion of deaths per hospitalized case observed in laboratory-confirmed surveillance data.
-From April 2009 to April 10, 2010 – the entire season – H1N1 – rounded estimates only
- Infections – Median estimate 61 million, range [43, 89]
- Hospitalizations – Median estimate 274 000, range [195000, 403000]
- Deaths – Median estimate 12470, range [8870, 18300]
-Adjusted for under-ascertainment, this suggests a crude hospitalized case fatality rate of 4.6%, and a crude overall case-fatality rate of 0.0214%.
Case series of influenza hospitalizations or deaths
Finland, 1942
-Case series of staphylococcal cases “of interest” appear during a period of influenza epidemic in Boston. Cases presented to Boston City Hospital, except for 2 cases of “especial interest” from elsewhere. All cases had adequate bacteriologic evidence of staphylococcal pneumonia.
-Smith and Poland report 3 of 66 cases with diabetes. However, I could only detect 2 diabetic patients in 42 cases of staphylococcal pneumonia. Among these, 18 patients with acute staphylococcal pneumonia with rapid and complete pneumonia did not have clinical characteristics tabled. 11 patients with severe staphylococcal pneumonia survived – one of these was diabetic. The other diabetic patient died in the group of 7 patients with acute pneumonia complicating influenza. 6 patients had fatal organizing and fibrosing pneumonia, leading to death 15 to 56 days after onset of severe pulmonary symptoms.
-Several miscellaneous cases of staphylococcal infections of the lung, as well as some focal infections, are reported additionally. Why these are not enumerated with the others is not apparent. This case series is highly suspect for selection bias.
Giles, 1957
-Necropsy results for a case series of 46 patients admitted for pneumonia, in which influenza was either the primary or a contributing cause of death according to clinical judgement (influenza was only isolated from 8/14 specimens tested). Patients were selected from 53 deaths at City General Hospital in Stoke-on-Trent during an epidemic with a high attack rate in September-October, 1957.
-Staphylococcus aureus was isolated from lungs or bronchi in 15 necropsies.
-2/46 deaths occurred in patients with diabetes (4.3%).
-The fatality rate of patients admitted to hospital during the epidemic exceeded 25% despite intensive antibiotic therapy.
Martin, 1958
-Case series of deaths in Boston during the 1957 Asian influenza pandemic. 118 excess fatalities suspected, 32 cases reported out of 43 fatal cases suspected of being influenza-associated at the study sites. Cases had either a solid clinical link to influenza by case history, or laboratory evidence of influenza infection.
-15 cases were influenza without bacterial complication, 11 were post-influenza staphylococcal pneumonia, and 6 cases were post influenza bacterial pneumonia, non-staphylococcal.
-21/32 cases had chronic disease of “major proportions”. 4/32 cases were pregnant. 3/32 cases had a history of diabetes. All three diabetic patients were middle-aged males, aged 30-45.