Analyzed the data: FC EAB PRC MAW. Wrote the paper: AMB CH CA PB AG OR MGC. Interpreted findings in the context of the international literature and assisted in manuscript development: FC EAB PRC MAW. Collected case-patient information and interpreted findings in the context of Argentina's medical system: AMB CH CA PB LC AG OR MGC.
The authors have declared that no competing interests exist.
The apparent high number of deaths in Argentina during the 2009 pandemic led to concern that the influenza A H1N1pdm disease was different there. We report the characteristics and risk factors for influenza A H1N1pdm fatalities.
We identified laboratory-confirmed influenza A H1N1pdm fatalities occurring during June-July 2009. Physicians abstracted data on age, sex, time of onset of illness, medical history, clinical presentation at admission, laboratory, treatment, and outcomes using standardize questionnaires. We explored the characteristics of fatalities according to their age and risk group.
Of 332 influenza A H1N1pdm fatalities, 226 (68%) were among persons aged <50 years. Acute respiratory failure was the leading cause of death. Of all cases, 249 (75%) had at least one comorbidity as defined by Advisory Committee on Immunization Practices. Obesity was reported in 32% with data and chronic pulmonary disease in 28%. Among the 40 deaths in children aged <5 years, chronic pulmonary disease (42%) and neonatal pathologies (35%) were the most common co-morbidities. Twenty (6%) fatalities were among pregnant or postpartum women of which only 47% had diagnosed co-morbidities. Only 13% of patients received antiviral treatment within 48 hours of symptom onset. None of children aged <5 years or the pregnant women received antivirals within 48 h of symptom onset. As the pandemic progressed, the time from symptom-onset to medical care and to antiviral treatment decreased significantly among case-patients who subsequently died (p<0.001).
Persons with co-morbidities, pregnant and who received antivirals late were over-represented among influenza A H1N1pdm deaths in Argentina, though timeliness of antiviral treatment improved during the pandemic.
In April 2009, pandemic influenza H1N1 2009 (influenza A H1N1pdm virus emerged in Mexico and the United States
On June 15th 2009, the first fatal influenza A H1N1pdm case in Argentina was confirmed
On June 26th 2009, the National Ministry of Health of Argentina (NMHA) created the National Commission for the Assessment of Influenza A (H1N1) to assess clinical aspects of influenza A H1N1pdm illness among fatalities, adequacy and timeliness of treatment, and possible risk factors for severe illness
In April 2009, the Government of Argentina activated the national Emergency Situation Room (ESR). Each province reported laboratory and epidemiological data on confirmed influenza A H1N1pdm fatalities and hospitalizations through the National Health Surveillance System and from laboratories performing real-time reverse-transcription polymerase-chain-reaction (rRT-PCR) for influenza A H1N1pdm through the Laboratory Surveillance System
For this study, a confirmed fatal case was defined as a patient who tested positive for influenza A H1N1pdm and who died in the period June 15-July 31 2009 (i.e. the peak of the pandemic). To identify cases, we searched a list of influenza A H1N1pdm laboratory-confirmed fatalities reported to the ESR by private and public institutions from the city of Buenos Aires and the seven provinces with the highest number of reported confirmed cases (i.e. Buenos Aires, Santa Fe, Córdoba, Neuquén, Río Negro, Tucumán, and Entre Ríos).
Physicians abstracted data on age, sex, medical history, comorbidities (i.e. chronic pulmonary, cardiovascular, renal, hepatic, hematological, metabolic, neurologic, immunologic and neonatal disorders), selected risk factors (e.g. obesity, defined as BMI>30 or subjectively assessed; pregnancy, alcoholism, and smoking), previous hospitalizations, signs and symptoms, clinical presentation, diagnosis at admission, duration of hospitalization and intensive care, radiographic findings, use of oseltamivir, and laboratory results using a standardized form. Nosocomial influenza A H1N1pdm virus infection was defined as a patient who developed respiratory symptoms >48 hours after admission for a non-respiratory cause and who later tested positive for influenza A H1N1pdm. Organ failures were defined according to international definitions
Respiratory specimens were collected from suspected cases and were tested for influenza A H1N1pdm by rRT-PCR assay initially in Argentina's National Reference Laboratory. As the pandemic progressed, an additional 18 laboratories were trained to use this technique and provided data for the study.
Differences in categorical variables among the three age groups (i.e.<5, 5–49, and >50 years) were analyzed by Χ2 tests and Fisher's exact test. Student t-tests and one-way analysis of variance (ANOVA) were used to compare means and Wilcoxon Rank sum test to compare medians.
To maintain data confidentiality, unique identifiers on medical records were coded. Institutional review board approval was not required as the NMHA empowered the commission to confidentially review medical records of influenza A H1N1pdm fatalities through a ministerial resolution
During 2009, 626 patients died with laboratory-confirmed influenza A H1N1pdm infection in Argentina
The remaining 332 fatalities had a median age of 36 years (IQR = 13–53 years) and 177 (53%) were male. Children aged <18 years accounted for 93 (28%) of fatalities, those aged <5 years comprised 48 (52%), and infants aged less <6 months comprised 16 (33%). Although more fatalities were reported among patients aged 19–49 years, laboratory-confirmed influenza A H1N1pdm fatalities per 100,000 population were more common among children aged <5 years and persons aged 50–64 years (
Fatalities reportedN = 332 | Fatalities reported (%) | Population |
Population (%) | No. fatalities reported per 100,000 pop | |
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48 | 14 | 3,349,278 | 9 | 1.4 |
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45 | 14 | 9,442,608 | 26 | 0.5 |
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134 | 40 | 15,241,760 | 42 | 0.9 |
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75 | 23 | 4,638,864 | 13 | 1.6 |
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30 | 9 | 3,587,620 | 10 | 0.8 |
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177 | 53 | 17,659,072 | 49 | 1.0 |
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155 | 47 | 18,601,058 | 51 | 0.8 |
Argentina census data (INDEC. Censo Nacional de Población, Hogares y Viviendas 2001).
Thirty fatalities were not hospitalized for influenza symptoms but rather acquired nosocomial influenza A H1N1pdm infections. Excluding these cases, the most common symptoms at admission were dyspnea (94%), cough (93%), and history of fever (85%). During admission, most patients had elevated respiration rates (73%) and heart rates (69%). On auscultation, crackles were more common among fatalities aged ≥5 years compared to fatalities <5 years (89% vs. 63%, p<0.01). Anemia was present in 54% of patients, and more common among those aged <5 years (67%, p<0.01) (
Age groups (years) | <5N = 48 | 5–49N = 179 | 50+N = 105 | All agesN = 332 |
N/total num of charts with data (%) |
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7/48 (13) | 17/179 (9) | 6/105 (6) | 30/332 (8) |
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25/30 (83) | 118/132 (89) | 59/76 (78) | 202/238 (85) |
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34/38 (89) | 133/141 (94) | 87/91 (96) | 254/270 (94) |
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14/19 (75) | 124/133 (93) | 84/88 (96) | 222/240 (93) |
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4/21 (19) | 34/96 (35) | 13/66 (20) | 51/183 (28) |
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1/4 (25) | 28/48 (58) | 15/39 (38) | 44/91 (48) |
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1/6 (17) | 18/55 (33) | 10/37 (27) | 29/98 (30) |
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5/32 (16) | 68/135 (50) | 36/86 (42) | 109/253 (43) |
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24/30 (80) | 90/120 (75) | 50/75 (67) | 164/225 (73) |
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31/37 (84) | 113/148 (76) | 47/92 (51) | 191/277 (69) |
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6/13 (46) | 16/138 (12) | 11/92 (12) | 33/243 (14) |
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19/30 (63) | 121/132 (92) | 70/80 (88) | 210/242 (87) |
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17/27 (63) | 39/88 (44) | 40/64 (63) | 96/179 (54) |
Unless otherwise stated.
Median (IQR).
Elevated respiration rate was defined as more than 40 breaths per minute for patients less than 5 years old and 25 breaths per minute for patients 5+ years old.
Elevated resting heart rate was defined as more than 120 beats per minute for patients less than 5 years old and 100 beats per minute for patients 5+ years old.
Low systolic tension was defined as <90 mmHg.
Hematology | ||||
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8/31 (26) | 38/124 (31) | 20/85 (24) | 66/240 (28) |
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13/31 (42) | 25/124 (20) | 30/85 (35) | 68/240 (28) |
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15/21 (71) | 56/71 (79) | 38/41 (93) | 109/133 (82) |
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28/41 (68) | 66/162 (41) | 44/99 (44) | 138/302 (54) |
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6/25 (24) | 40/81 (49) | 19/53 (36) | 65/159 (41) |
Chemistry | ||||
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9/19 (47) | 40/99 (40) | 51/70 (73) | 100/188 (53) |
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7/13 (54) | 26/55 (47) | 16/35 (46) | 49/103 (48) |
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5/13(38) | 14/56 (25) | 8/31 (26) | 27/100 (27) |
Acid-base | ||||
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19/32 (59) | 125/146 (86) | 78/92 (85) | 222/270 (82) |
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15/20 (75) | 41/102 (40) | 40/77 (52) | 96/199 (48) |
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10/19 (53) | 18/101 (18) | 22/77 (29) | 50/197 (25) |
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23/33 (70) | 132/147 (90) | 86/94 (92) | 241/274 (88) |
Lymphopenia was defined as <3000 cells/ml for patients under 5 years old, <2000 cells/ml for patients 5-12 years old and <1,500 cells/ml for patients over 12 years old.
Anemia was defined as less than 11 g/dl of hemoglobin (Hb) for patients less than 5 years old and for pregnant women (>15 years old), less than 11.5 g/dl Hb for patients 5–12 years old, less than 12 g/dl Hb for patients 12–15 years old and for non-pregnant women (>15 years old), and less than 13 g/dl Hb for men 15 years and older.
“Acidosis or hypoxemia” is defined as pH under 7.36 or oxygen saturation less than 96%.
Among 176 patients with admission radiographs, (79%) had bilateral chest infiltrates, 71 (40%) had consolidation, 61 (35%) had interstitial pattern, 37 (21%) had both, and six (3%) had other findings (
X-Rays patterns at admission | ||||
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14/26 (54) | 37/93 (40) | 20/57 (35) | 71/176 (40) |
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12/14 (86) | 26/36 (72) | 7/20 (35) | 45/70 (65) |
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8/26 (31) | 29/93 (31) | 24/57 (42) | 61/176 (35) |
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8/8 (100) | 28/29 (97) | 23/24 (96) | 59/61 (97) |
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3/26 (12) | 23/93 (25) | 11/57 (19) | 37/176 (21) |
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3/3(100) | 21/23 (91) | 10/11 (91) | 34/37 (92) |
Primary Diagnosis at admission (includes patients that developed influenza A H1N1pdm nosocomial infections) | ||||
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26/48 (54) | 133/179 (74) | 78/105 (74) | 237/332 (71) |
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16/48 (33) | 28/179 (16) | 21/105 (20) | 65/332 (20) |
6/48 (10) | 18/179 (13) | 6/105 (6) | 30/332 (9) |
COPD, Asthma, atelectasis, tuberculosis, respiratory failure.
Fever syndrome, septic shock, leukemia, gastrointestinal problems, pregnancy, HIV/AIDS.
Of 304 patients admitted for influenza A H1N1pdm-associated illness (excluding nosocomial infections), the median time from symptom onset to admission was five days (IQR, 3–7 days). Most patients (299 [95%] of 315) needed ICU admission and, 292 were mechanically ventilated for a median of six days (IQR, 2–12 days). Among the 252 patients with available information on the start date of their mechanical ventilation, 207 (82%) were mechanically ventilated within the first 24 hours of admission to intensive care (
<5 years | 5–49 years | >50 years | Total | |
N = 48 | N = 179 | N = 105 | N = 332 | |
Antiviral use (ATV) | N (%) total | |||
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40/48 (83) | 156/179 (87) | 94/105 (90) | 290/332 (87) |
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0/36 (0) | 23/139 (17) | 12/79 (15) | 33/253 (13) |
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6/30 (20) | 56/112 (50) | 43/68 (63) | 105/210 (50) |
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18/33 (55) | 103/129 (80) | 62/79 (78) | 183/241 (76) |
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46/47 (98) | 162/170 (95) | 91/98 (93) | 299/315 (95) |
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47/47 (100) | 160/174 (92) | 85/99 (86) | 292/320 (91) |
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0 (0–1)/38 | 0 (0–0)/140 | 0 (0–0)/73 | 0 (0–0)/233 |
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7 (4–13)/41 | 6 (2–12)/152 | 5 (2–11)/81 | 6 (2–12)/252 |
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1 (0–3)/31 | 2 (0–4)/116 | 3 (1–5)/75 | 2 (0–4)/222 |
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6 (3–10)/29 | 2 (0–5)/103 | 1 (0–5)/64 | 2 (0–5)/196 |
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6 (2–9)/27 | 4 (3–6)/125 | 5 (3–7)/79 | 5 (3–7)/231 |
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1 (0–4)/27 | 0 (0–2)/118 | 0 (0–1)/73 | 0 (0–2)/218 |
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0 (0–2.5)/32 | 1 (0–2)/127 | 0 (0–1)/75 | 0 (0–1)/234 |
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15 (8.5–22)/32 | 12 (7–20.5)/140 | 13 (7–20)/87 | 13 (7–20)/259 |
eleven case-patients were ventilated outside of the ICU because of space-limitations.
excluding influenza A H1N1pdm nosocomial infections.
The most frequent organ failure was respiratory failure (97%). Additionally, 85% of the patients met the criteria for acute respiratory distress syndrome (ARDS) during their hospitalization. These patients had hypoxemia [median Pa/FiO2 87 (IQR: 60–129)], hypercapnia [median PaCO2 54 (IQR: 43–72), and acidosis [median pH 7.24 (IQR: 7.10–7.33) requiring elevated concentration of oxygen (FiO2 100% in 72% of cases), maximal high positive end expiratory pressure [median 15 (IQR: 10–18)] and use of ventilation in prone position or alveolar recruitment maneuvers in 41% of patients. Hemodynamic failure requiring vasoactive drugs occurred in 54% of patients. Renal failure was present in 134 (43%) of the 312 patients with available data and 29% of these required dialysis. Of the 134 patients with renal failure, 31 (23%) had previous chronic renal failure of which eight [6%] were on chronic hemodialysis. Six (13%) of 47 children aged <5 years with available data developed renal failure compared to 128 (48%) of 265 persons aged ≥5 years (p<0.0001).Hematologic failure was diagnosed in 44%, hepatic failure in 5% and multiorgan failure in 71% of influenza A H1N1pdm fatalities.
Of all 332 patients, 290 (87%) received antiviral treatment; 183 (76%) ≤2 days of admission but only 33 (13%) of 253 with information on timing of administration received antivirals ≤48 hours of symptom onset. None of the 48 fatalities aged <5 years received antivirals ≤48 hours of symptom onset; 20% of these children received antivirals ≤48 hours of a doctor's visit, and only 55% received antivirals ≤48 hours of hospitalization compared to at least 78% in older age groups (
As the pandemic progressed, the mean time from symptom onset to first doctor visit and symptom onset to hospitalization among fatalities decreased (p<0.001). Similarly, the mean time from symptom onset to antiviral treatment decreased from 19 days during epidemiologic week 22 to four days during week 28 (p<0.001). The time from the first doctor visit to antiviral treatment also decreased as the pandemic progressed (p<0.001) while the time from hospitalization to antiviral treatment remained brief (
At least one comorbidity
Age groups | <5 | 5–49 | 50+ | Total |
N = 48 | N = 179 | N = 105 | N = 332 | |
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N (%) total | |||
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20/48 (42) | 29/152 (19) | 33/94 (35) | 82/294 (28) |
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0/41 (0) | 11/142 (8) | 5/89 (6) | 16/272 (6) |
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5/41 (12) | 16/154 (10) | 35/94 (37) | 56/289 (19) |
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2/41 (5) | 11/151 (7) | 18/88 (21) | 31/280 (11) |
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1/39 (3) | 8/151 (5) | 4/85 (5) | 13/275 (5) |
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3/38 (8) | 22/148 (15) | 8/88 (9) | 33/274 (12) |
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3/42 (7) | 34/156 (22) | 35/91 (39) | 72/289 (25) |
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0/40 (0) | 22/150 (15) | 22/87 (25) | 44/277 (16) |
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4/42 (10) | 43/163 (26) | 24/92 (26) | 71/297 (24) |
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0/38 (0) | 10/155 (7) | 1/85 (1) | 11/278 (4) |
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29/48 (60) | 34/160 (21) | 12/93 (13) | 75/301 (25) |
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9/48 (19) | 33/160 (21) | 12/93 (13) | 54/301 (18) |
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17/48 (35) | n/a | n/a | n/a |
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39/48 (81) | 115/170 (68) | 85/101 (84) | 239/319 (75) |
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0/40 (0) | 54/154 (35) | 34/82 (42) | 88/276 (32) |
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1/40 (3) | 28/153 (18) | 58/94 (62) | 87/287 (30) |
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n/a | 35/171 (20) | 29/103 (28) | 64/321 (20) |
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n/a | 9/145 (6) | 15/86 (17) | 24/269 (9) |
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n/a | 6/142 (4) | 2/81 (3) | 8/261 (3) |
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n/a | 20/91 (22) | 0/44 (0) | 20/155 (13) |
Comorbidities as defined by the Advisory Committee on Immunization Practices 10.
Including asthma.
Excluding hypertension.
Including diabetes.
Persons who have immunosuppression (including immunosuppression caused by medications or by human immunodeficiency virus, HIV).
Persons who have any condition (e.g., cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders) that can compromise respiratory function or the handling of respiratory secretions or that can increase the risk for aspiration.
Including cerebrovascular disease, cerebral palsy, epilepsy, down syndrome, neurochronic disease.
Does not include former and passive smokers.
Women only.
We identified 16 pregnant women and four postpartum women among fatalities. Four of the pregnant women were in their second trimester while 11 were in their third trimester. Eight delivered by caesarean section after being admitted to the ICU, two whom had stillbirths. Pregnant women had significantly longer ICU stays than non-pregnant women aged 15–44 years (11 vs. 4 days, p = 0.01). One pregnant and two postpartum women did not receive any antiviral treatment during the course of their illness. Among the 17 pregnant or postpartum women that received antivirals, none received them within the recommended 48 hours after illness onset but a median of seven days (IQR: 5–9 days) later. Fifty percent received antivirals <1 day after hospitalization (
Pregnant andPostpartum (N = 20) | Non-pregnant(N = 44) | |
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26.5 (19–41) | 32.5 (16–44) |
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4 | n/a |
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16 | n/a |
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4/15 | n/a |
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11/15 | n/a |
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2/16 | n/a |
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8/16 | n/a |
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13/14 | n/a |
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1/15 | 9/40 (23%) |
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1/17 | 3/39 (8%) |
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0/16 | 2/40 (5%) |
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0/16 | 4/39 (10%) |
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3/18 | 3/37 (8%) |
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3/18 | 16/39 (41%) |
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1/18 | 12/41 (29%) |
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2/18 | 4/39 (10%) |
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9/19 | 29/42 (70%) |
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2/16 | 16/38 (42%) |
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2/16 | 7/40 (18%) |
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17/20 | 39/44 (89%) |
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0/17 | 4/29 (14%) |
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7 (5–9) | 5 (3–7) |
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4 (2.5–6) | 1 (0–5) |
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1 (1–3) | 0 (0–2) |
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4 (2–6) | 4 (2–5) |
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11 (6–16) | 4 (2–12) |
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14 (13–17) | 9 (5–18) |
Most fatal cases presented to the hospital with acute severe respiratory compromise or ARDS and required immediate mechanical ventilation with respiratory failure as their main cause of death. The median age of fatalities was consistent with those found in other influenza A H1N1pdm studies
Two-thirds of all cases had at least one comorbidity as defined by ACIP
Even though the government of Argentina recommended oseltamivir treatment to high-risk persons
The high proportion of pregnant or postpartum women in our case-series of decedents is concordant with reports that identify pregnancy as a risk factor for severe influenza illness and death
Although other studies have shown a high frequency of dyspnea in critically ill patients, our analyses demonstrates our case-patients also frequently had tachypnea (73%), tachycardia (69%) and acidosis and/or hypoxemia (88%) on admission. Gastrointestinal symptoms were more frequently reported than in adults infected with seasonal influenza but not as frequently as in other influenza A H1N1pdm studies
During the pandemic, an insufficient number of ICU beds were available for all patients. Critically ill patients occasionally received mechanical ventilation outside the ICU, at the emergency department or special facilities
Our analysis indicates that time from symptom onset to clinic visit and to hospitalization decreased as the pandemic progressed. Time to antiviral treatment also decreased during the first two weeks of the study. These data suggest that affected persons sought care earlier and physicians used antivirals more rapidly as the pandemic progressed and may explain why the case fatality proportion of hospitalized patients decreased from a peak at the beginning of the pandemic. The initial delay in health seeking may have been caused by high risk persons that did not suspect that they had influenza illness or that were not aware of the need to seek care within 48 hours of symptom onset when antivirals are most effective. The initial delay in treatment could have been caused by unavailability of antivirals or by primary care physicians unfamiliar with their use. In Argentina, only a small stockpile of oseltamivir was available at the beginning of the pandemic which was insufficient to treat all patients once influenza A H1N1pdm spread throughout the country.
Our study has several limitations. Our case-series design did not allow us to collect information from controls to further substantiate whether potential risk factors were indeed associated with death from H1N1pdm. The data obtained was limited to non-standardized medical records and there was no opportunity to confirm details with family members. Due to the limited availability of laboratory testing during the study period, the number of confirmed fatalities represented only about half of the currently confirmed fatalities and may not be representative of other fatalities during this period or of those who occurred at home. Moreover, we only assessed hospitalized laboratory-confirmed influenza A H1N1pdm fatalities for which we had medical records, and these cases might have manifested differently to those occurring at home or those not tested for influenza. Laboratory samples and tests did not follow a study protocol but represented the choices made by clinicians during the management of patients. Our study did not include autopsy data. Several parameters that define risk factors and underlying conditions, such as height and weight data, smoking history and alcohol consumption, were not available for all case-patients. We were unable to compare risk factors for death compared to severe disease and the effect of antiviral treatment as we did not review charts from surviving hospitalized patients.
After the study was conducted, Argentina has emphasized protecting young children and pregnant women. The 2010 monovalent influenza A H1N1pdm influenza vaccination campaign in Argentina aimed at a 95% coverage among pregnant women and 85% coverage among children aged <4 years
The authors thank Oreste Luís Carlino, Adriana Sucari, Manuel Klein, Carlota Russ, Carolina Domínguez Balanzat, Mabel Moral, and Luis Gerardo Castellanos, Horacio Echenique. We also acknowledge PAHO-Argentina staff support (i.e. Marcia Moreira, Osvaldo Rico, and Ana Cabrera), and the Argentinean national and local directors of epidemiology, the hospital Directors and the hospital staff for their dedicated support in the process of data collection.