Special Articles

The critically ill child with novel H1N1 inuenza A: A case series*
Justin L. Lockman, MD; William A. Fischer, MD; Trish M. Perl, MD, MSc; Alexandra Valsamakis, MD, PhD; David G. Nichols, MD
Objective: To describe the presentation, course, and outcome of critically ill children with novel H1N1 inuenza disease. Design: Retrospective case series. Setting: Pediatric intensive care unit in an urban tertiary academic center. Patients: Thirteen consecutive patients admitted between June 2009 and August 2009 and known or subsequently found to be infected with novel H1N1 inuenza A. Interventions: None. Measurements and Main Results: Clinical, laboratory, and radiographic data were reviewed. The patients were predominantly male (62%), aged 5 months to 21 yrs, and most (92%) had known risk factors for severe disease. Direct uorescent antibody testing had a high false-negative rate (62%) and delayed treatment in some cases. The respiratory illness presented clinically with both bronchoconstriction and alveolar consolidation to varying degrees. Bacterial superinfection occurred frequently (23%). Fortysix percent of patients required mechanical ventilation and 23% required inotropic support for hypotension. None of the patients in this series required extracorporeal membrane oxygenation. Intensive care unit length of stay did not differ between an early (within 48 hrs) oseltamivir treatment group (length of stay, 4.2 4.4 days) vs. a late treatment group (length of stay, 6.8 8.8 days). All patients survived to hospital discharge. Conclusions: Underlying chronic illness (especially respiratory illness) seems associated with critical novel H1N1 inuenza disease in children. Respiratory manifestations are highly variable among patients and within a single patient involving both bronchoconstriction and alveolar disease. Therapies must be individualized and rapidly adjusted. The duration of critical illness was not different between early and late treatment groups. Whether this is reective of sample size or indicative of the importance of therapeutic intervention at any time early during infection in critically ill patients is unclear. Bacterial superinfection was more common than previously reported for seasonal inuenza A. Moderate novel H1N1 inuenza disease, including respiratory failure and hypotension, had 100% survival in our series. (Pediatr Crit Care Med 2010; 11:173178) KEY WORDS: inuenza, human; inuenza A virus, H1N1 subtype; intensive care units, pediatric; critical illness; mechanical ventilation; superinfection

etween March and June 2009, an out-of-season inuenza outbreak, rst detected in Mexico and then worldwide, led to identication of a novel virus, H1N1 inuenza A virus (nH1N1 inuenza) (1). This triple-reassortant inuenza, containing genes from swine, avian, and human inuenza lineages, is similar to the 1918 inuenza pandemic virus and has been described as the greatest pandemic threat since the emergence of Inuenza A (H3N2) virus in 1968 (2). Like seasonal inuenza disease, nH1N1 inuenza disease seems to have increased infection rates among pedi-

atric and young adult patients and a variable spectrum of disease severity. Although the full virulence of the novel inuenza strain will not be known until a greater proportion of the population is infected, we report the rst case series of critically ill children with nH1N1 inuenza disease based on patients admitted to our pediatric intensive care unit (PICU) during the spring and summer of 2009. The Johns Hopkins School of Medicine Institutional Review Board reviewed and approved the study.

MATERIALS AND METHODS Setting and Case Identication

*See also p. 295. From the Departments of Anesthesiology and Critical Care Medicine (JLL, DGN), Pediatrics (DGN), Medicine (WAF, TMP), and Pathology (AV), The Johns Hopkins University School of Medicine, Baltimore, MD. The authors have not disclosed any potential conicts of interest. For information regarding this article, E-mail: dnichols@jhmi.edu Copyright 2010 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0b013e3181ccedae

The Johns Hopkins Hospital Childrens Center is a regional Childrens Hospital that serves Maryland and the surrounding area. The 26-bed PICU cares for 1300 children annually with an average length of stay of 5.7 days. Hospital Epidemiology and Infection Control monitors health care-associated infections and epidemiologically signicant organisms for The Johns Hopkins Hospital Childrens Center, using a system that combines administrative, microbiological, radiologic,

and other data sources to produce reports (TheraDoc, Inc., Salt Lake City, UT). Because of an active respiratory virus prevention program, systematic surveillance and prevention planning includes prospective tracking of inuenza. All patients admitted to The Johns Hopkins Hospital Childrens Center during respiratory season (including the present pandemic) are tested for respiratory virus infection. Nasopharyngeal aspirates are tested, using direct uorescent antibody (DFA) for inuenza A, inuenza B, respiratory syncytial virus, human metapneumovirus, adenovirus, and parainuenza virus types 13. All residual specimens were stored at 80C. Shell vial (R-Mix Too, Diagnostic Hybrids Inc., Athens, OH) and tube cultures (rhesus monkey kidney and A549 cells, Diagnostic Hybrids, Inc.) were inoculated in parallel with DFA. Shell vials were stained at 48 hrs for all viruses detected by DFA, except human metapneumovirus. Tube cultures were examined daily for 7 days, then weekly for an additional 2 wks until cytopathic effect was observed. All samples from inhospital patients identied as inuenza A by DFA, shell vial, or tube culture were sent to the Maryland Department of Health and Mental Hygiene for conrmatory nH1N1 testing, using the U.S. Centers for Disease Control and

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Prevention (CDC) reagents for reverse transcription/real-time polymerase chain reaction.

Data Collection, Denitions, and Analysis

The nH1N1 inuenza-infected patients in The Johns Hopkins Hospital PICU were identied from the Hospital Epidemiology and Infection Control database. Clinical information on each patient was veried and supplemented by medical record review with a standardized data abstraction form. Demographic data, past medical history, presenting symptomatology, microbiological and laboratory data, radiographic studies, and treatment, and outcome data were collected. Patients were considered to have clinical evidence of pulmonary bacterial superinfection if they developed new radiographic ndings consistent with bacterial pneumonia, such as lobar consolidation plus recurrent fever, dyspnea, tachypnea, increased or purulent secretions (3) after initial clinical improvement. Patients were considered to have evidence of bronchospasm if they clinically demonstrated wheezing or improvement with -agonist therapy. Patients treated with oseltamivir were divided into early and late treatment groups based on timing of therapy relative to symptom onset ( 48 hrs or 48 hrs, respectively). SD, where Data are presented as mean appropriate. Analysis of variance was used to determine statistical signicance of differences between early and late treatment groups. A p .05 was considered signicant.

RESULTS Illustrative Cases Patient 1

A 17-yr-old female with known sickle cell anemia, hypertension secondary to sickle cell nephropathy, and asthma presented to our emergency department with fever, hypoxia, dyspnea, and chest pain after a routine outpatient transfusion. No abnormalities were noted on chest radiography. Respiratory and blood cultures were obtained. She was admitted for pain management and antimicrobials and was discharged home 48 hrs later after clinical improvement. The patient returned to the emergency department several days after discharge with recurrent fever, cough, dyspnea, lethargy, vomiting, and diarrhea. Hemoglobin was noted to be 4.7 g/dL and a repeat chest radiograph demonstrated a left upperlobe consolidation consistent with acute
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chest syndrome. The patient was admitted to the PICU. The DFA for inuenza was negative, and she improved clinically after double-volume exchange transfusion and initiation of bilevel positive airway pressure ventilation and antibacterial therapy. However, ongoing low-grade hemolysis was suspected due to decreasing hemoglobin levels and mild hematuria. On day 3, she developed severe dyspnea and was intubated for respiratory failure. Chest radiography showed diffuse alveolar inltrates consistent with acute respiratory distress syndrome. Intravenous corticosteroids were added to bronchodilator therapy and antibacterial coverage was broadened. The patient subsequently developed oliguric renal failure and hypotension requiring inotropic therapy, and she continued to have unexplained high fever and bronchospasm. On day 10 of illness and day 5 after obtaining the nasopharyngeal aspirates on admission, inuenza A (nH1N1 inuenza) was isolated from tube culture and oseltamivir therapy was begun via nasogastric tube. Her course was notable for paroxysms of severe cough with hypoxia requiring neuromuscular blockade in addition to deep sedation/anesthesia while intubated. Renal function ultimately recovered to baseline without renal replacement therapy. She remained intubated for a total of 14 days and remained in the intensive care unit for a total of 26 days. On hospital day 32, the patient was transferred to a rehabilitation hospital and was subsequently discharged. She continues outpatient transfusion therapy and is neurologically intact.

culture grew inuenza A (nH1N1 inuenza) at 3 days; the patient completed a 5-day course of oseltamivir.

Patient 3
A 14-yr-old female with congenital cytomegalovirus infection and associated cerebral palsy, mental retardation, obstructive sleep apnea (requiring overnight continuous positive airway pressure), and gastrostomy tube dependence was admitted with increased frequency of emesis. After admission, she developed progressive respiratory distress requiring intubation and transfer to the PICU for mechanical ventilation. A nasopharyngeal aspirate was sent due to the decline in respiratory status and the DFA was positive for inuenza A (nH1N1 inuenza). Oseltamivir therapy was initiated (approximately 24 hrs after onset of initial symptoms). The patient required invasive mechanical ventilation for 7 days and remained in the PICU for 16 days. Because airway instrumentation occurred before the suspicion of viral illness, the patient was not appropriately isolated and multiple staff members on the inpatient oor, the rapid response team, and the ICU team were exposed to inuenza.

Summary Results for the Entire Series

Between June 1, 2009 and August 7, 2009, we diagnosed 140 patients 264 months (22 yrs) of age with nH1N1 infection at The Johns Hopkins Hospital; 13 (9.3%) required admission to the PICU (three patients, aged 20 21 yrs, were admitted to adult ICUs). All patients were exposed to nH1N1 in the community. The median age was 114 months (range, 5263 months), with a male predominance (62% male) (Table 1). Almost all patients had underlying comorbid illness and risk factors for complications of inuenza, of which asthma was most prevalent (85%) followed by neuromuscular disease (38%). Based on the Pediatric Risk of Mortality III score (4.5 4.36), the severity of illness at admission to the PICU was mild to moderate (4). DFA proved highly insensitive with a 62% false-negative rate. DFA detected only 38% of cases; an additional 38% of cases were detected at 48 hrs by shell vial. Twenty-three percent of cases were detected only by tube culture. The mean times to diagnosis of all samples requiring shell vial or tube culture were 5.3 ( 2.8) days and 2.4 ( 1.2) days from symptom onset and PICU admission, respectively.
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Patient 2
A 21-yr-old female with a history of congenital human immunodeciency virus infection complicated by encephalopathy (with paraplegia), lymphocytic interstitial pneumonitis, and poor compliance with medical therapy presented with 2 days of fever, tachypnea, pharyngitis, and cough. Absolute CD4 count on admission was 470/mm3. She was admitted to the PICU for management of hypoxia, dyspnea, and hypotension requiring transient vasopressor therapy. Antimicrobial therapy, including oseltamivir, was initiated despite negative DFA results because chest radiography demonstrated increased bilateral perihilar markings consistent with viral infection compared to a previous study. Within 24 hrs, the patient had returned to her baseline respiratory condition and was downgraded to a noncritical hospital bed. Shell vial culture was negative, but tube

Table 1. PICU nH1N1 patient demographic characteristics Age, mos Sex, % male Race, % black, % white, % other Risk factors for severe disease presenta, % Risk factors/comorbid illnesses, % Pulmonary disease, including asthma Hematologic disease, including sickle cell anemia Neurologic/neuromuscular disease Immunosuppression Obesityb PRISM III score, rst 24 hrs (4) Days from onset of symptoms to ICU admission Days from symptom onset to diagnosis Days from ICU admission to diagnosis Number of cases leading to documented staff exposure Mean 127 91 Median 114 Range 5263 62 46, 38, 15 92

Table 2. Laboratory data during PICU admission for patients with nH1N1 infection False-negative DFA test, % False-negative DFA and shell vial (48 hrs) culture, % Days from NPA to positive tube culture (among those false negative at 48 hrs) Admission total white blood cell count, #/mm3 n 12 Minimum total leukocyte count, #/mm3 n 12 Maximum total leukocyte count, #/mm3 n 12 Admission lymphocyte count, #/mm3 n 11 Maximum blood urea nitrogen, mg/dL n 12 Maximum creatinine, mg/dL n 12 Maximum AST, U/L n 10 Maximum ALT, U/L n 10 62 23

Table 3. Life-support and treatment data for PICU nH1N1 patients Treatment with oseltamivir, % Time from onset of symptoms to administration of oseltamivir, days Oseltamivir treatment Within 48 hrs of symptom onset (early), % After 48 hrs of symptom onset (late), % Antimicrobial treatment for bacterial superinfection, % Antibacterial treatment timing among superinfection group, days since symptom onset Mechanical Ventilation (invasive and noninvasive), % Endotracheal intubation and invasive mechanical ventilation, % of total, % of patients with mechanical ventilation Noninvasive mechanical ventilation, % of total, % of patients with mechanical ventilation Nadir PaO2/FIO2 among intubated patients, torr [kPa]a Peak oxygenation index among intubated patients Administration of inhaled -agonist bronchodilator therapy, % Administration of systemic corticosteroids, % of total, % of bronchodilator group Administration of therapeutic intravenous magnesium, % of total, % of bronchodilator group Hypotension requiring inotropic drugs, % 85 Mean 3.6 3.1 Range 010

Mean 3.7 1.2 Range 35

45 55 23

85 15

Mean 8724

4439

Range 299018,940 Mean 7048 3939 Range 231016,140 Mean 11,675 6073 Range 299018,940 Mean 1473 1110 Range 4403977 Mean 14 13 Range 454 Mean 0.7 0.7 Range 0.22.8 Mean 52 41 Median 34 Range 19131 Mean 41 41 Median 20 Range 14152

38 23 31 Mean 4.2 4.4 Range 015 Mean 3.2 2.0 Range 17 Mean 4.4 2.6 Range 110 Mean 1.5 1.5 Range 05 1 (8%)

3.0

2.0

46

31, 67

15, 33

PICU, pediatric intensive care unit; nH1N1, novel H1N1 inuenza A virus; PRISM, Pediatric Risk of Morality; ICU, intensive care unit. a Adapted from the Centers for Disease Control and Prevention recommendations (5); bobesity based on body mass index (BMI) 90th percentile for age. Where BMI data unavailable, weight for age 90th percentile was used.

Mean 213 105 Range 98364 Mean 16 7.3 Range 1122 77

The mean times to diagnosis of samples requiring tube culture were 7.3 ( 3.1) days and 3.3 ( 1.5) days from symptom onset and PICU admission, respectively. Laboratory data were consistent with viral infections. The average admission total leukocyte count was in the normal range (8724 4449/mm3); some patients presented with leukopenia or leukocytosis (Table 2). Lymphopenia was common with the mean lymphocyte count of 1473 ( 1110)/mm 3 at admission. Hepatic transaminase enzymes and renal function tests were normal or mildly elevated during the PICU stay. Twenty-three percent (3 of 13 patients) of the study population presented with normal chest radiography and never developed any abnormality on chest radiography. Some patients with radiographic abnormalities on admission had multiple types of abnormalities. Of patients with abnormal admission chest radiographs, 60% (6 of 10) demonstrated
Pediatr Crit Care Med 2010 Vol. 11, No. 2

PICU, pediatric intensive care unit; nH1N1, novel H1N1 inuenza A virus; DFA, direct uorescent antibody; NPA, nasopharyngeal aspirates; AST, aspartate transaminase; ALT, alanine aminotransferase. One patient had no laboratory data collected. Sample size for each test as indicated.

54, 70

54, 70

increased interstitial markings consistent with viral disease, whereas 30% (3 of 10) revealed diffuse alveolar inltrates and 40% (4 of 10) had ndings consistent with hyperination. Thirty-one percent (4 of 13) of all patients already had evidence of lobar consolidation on chest radiography at PICU admission and one patient (8%) had a pleural effusion at admission. Peak radiographic ndings occurred at 4.6 ( 3.4) days after admission and consisted of diffuse alveolar inltrates in 70% (7 of 10) of patients with abnormal chest radiographs. Eighty-ve percent (11 of 13 patients) of patients with nH1N1 received antiviral therapy (Table 3); all treated patients received standard-dose oseltamivir. Among those treated, 45% (5 patients) were treated within 48 hrs of initial symptom onset (early treatment group) and 55% (6 patients) were treated after 48 hrs of symp-

23

PICU, pediatric intensive care unit; nH1N1, novel H1N1 inuenza A virus. a To convert torr to kPa, 0.133.

tom onset (late treatment group). Forty-six percent (6 of 13 patients) of the entire study population received mechanical ventilation, four patients via endotracheal tube and two patients by noninvasive methods (e.g., bilevel positive airway pressure). Consistent with the radiographic prevalence of increased interstitial markings and hyperination, a majority of patients (77%) also had symptoms of bronchospasm that were alleviated with -agonist therapy. More
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Table 4. Outcomes All Patients (N 13) Survival, % ICU length of stay, days (NS, p .583) Duration of mechanical ventilation (invasive or noninvasive), days (NS, p .273) Interval between oseltamivir and extubation, days (NS, p .270) 100 Mean 5.8 7.9 Median 2.0 Range 016 Mean 6.5 5.7 Median 6.0 Range 117 Mean 6.0 6.0 Median 7.0 Range 015 Early Treatment (N 5) 100 Mean 4.2 6.6 Median 1.0 Range 116 Mean 4.0 4.2 Median 4.0 Range 17 Mean 3.5 5.0 Median 3.5 Range 07 Late Treatment (N 6) 100 Mean 6.8 8.8 Median 3.5 Range 026 Mean 7.8 6.5 Median 6.0 Range 217 Mean 7.7 7.0 Median 7.0 Range 115

Variability in Respiratory Disease

A surprising aspect of this series was the variability of symptomatology among the most severely affected children. Both clinically and radiographically, our patients displayed features of alveolar consolidation/acute respiratory distress syndrome and reversible obstructive lung disease (bronchoconstriction). This combination proved a particular challenge in critical care management. In our case series, the severe bronchospasm was treated with intravenous magnesium sulfate, systemic corticosteroids, and short-acting -agonist therapy in 54%, 54%, and 77% of patients, respectively. The most severely affected patients also experienced intense coughing spells during invasive mechanical ventilation requiring both anesthetic doses of sedative hypnotic agents and (in three patients) persistent neuromuscular blockade. Given that management strategies for bronchospasm and acute respiratory distress syndrome are not well aligned, mechanical ventilation and management of critically ill children with nH1N1 infection proved to be challenging. When the composite picture included alveolar consolidation, hypoxemia, and bronchospasm, we utilized a strategy of high positive end-expiratory pressure, low tidal volume, and low ventilator breath frequency to maintain protective low lung volumes at the same time prolonging the expiratory phase to allow alveolar emptying and prevent air trapping. However, the management of these patients should be individualized and regularly reassessed and rapidly adjusted to reect the heterogeneous and labile nature of the lung involvement.

ICU, intensive care unit; NS, not signicant.

than half of patients received adjuvant therapies for bronchoconstriction, including therapeutic magnesium and/or systemic corticosteroids. Three patients (23%) required inotropic therapy for hypotension; echocardiography for two of these patients demonstrated normal left ventricular function. The third patient did not undergo echocardiography due to limited duration of vasopressor therapy. No patient required renal replacement therapy or extracorporeal support. Twenty-three percent (3 of 13 patients) of patients in this case series were treated for a suspected bacterial superinfection on the basis of clinical and radiographic ndings (Table 3). None of the bacterial cultures obtained from patients grew. Patient outcomes were divided into subgroups based on early treatment or late treatment (Table 4). ICU length of stay was 4.2 ( 6.6; median, 1.0) days and 6.8 ( 8.8; median, 3.5) days for the early and late treatment groups, respectively. Duration of mechanical ventilation for the early treatment group was 4.0 4.2 days compared with the late treatment group duration of 7.8 6.5 days. The differences in ICU length of stay and duration of mechanical ventilation were not statistically signicant between those who were part of the early or late treatment groups. All patients survived through hospital discharge.

variable from patient to patient and within a single patient involving bronchoconstriction and alveolar consolidation. Respiratory support and sedation therapies must be individualized and rapidly adjusted. 3) Diagnosis and treatment were often delayed, reecting initial inexperience with nH1N1 disease during the start of the pandemic. 4) The duration of critical illness was not different between early and late treatment groups although our patient numbers are small. 5) Bacterial superinfection occurred in one quarter of patients, more commonly than previously reported. 6) Moderate nH1N1 inuenza disease, including respiratory failure and hypotension, had 100% survival in our series.

Association With Underlying Chronic Illness

The CDC has described underlying conditions that, for seasonal inuenza disease, place patients at increased risk for complications (5). This series conrms the significant vulnerability of patients with comorbidities for nH1N1 inuenza infection. Ninety-two percent of patients admitted to our PICU with nH1N1 inuenza disease were previously known to have one of these high-risk conditions (Table 1), whereas only one patient was admitted with no signicant past history of disease. As this pandemic continues, additional data will likely emerge to better dene high-risk groups for nH1N1 inuenza; however, our data support the use of high-risk groups as dened in seasonal inuenza outbreaks as preliminary risk factors for critical illness in nH1N1 disease.

Delayed Diagnosis and Prevention of Disease

Sixty-two percent (8 of 13) of critically ill inuenza patients in this series had an initial negative DFA result. The low sensitivity of DFA and the subsequent reliance on culture for detection resulted in a delay in denitive diagnosis for these patients. As demonstrated in the case of Patient 1, viral tube culture is very sensitive but virus growth may require 5 days. Nucleic acid amplication tests, such as the CDCs real-time polymerase chain reaction assay, combine high sensitivity with faster time-to-result and, therefore, may play a more central role as the pandemic evolves (6, 7).
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DISCUSSION
The nH1N1 disease has primarily impacted young people, including children. The major ndings from this series are: 1) underlying chronic illness (especially respiratory illness) seems associated with critical nH1N1 inuenza disease in children. 2) The respiratory illness is highly
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The importance of detailed hospital disaster plans and staff preparedness cannot be underestimated. As demonstrated by patient 3, delayed diagnosis and failure to anticipate the possibility of an inuenza-related etiology for symptoms will lead to unnecessary staff exposure. We subsequently determined that our rapid response team would carry personal protective equipment to all off-unit events where intubation or other high-risk procedures may take place. Note that this practice is also not without risk, as it involves a delay in care as personal protective equipment is applied and decreased efciency of communication when members of the team are subjected to the noise and isolation of a Powered Air-Purifying Respiratory device. As noted by Aziz, it is essential for hospitals to prepare for pandemic inuenza with written (and rehearsed) disaster policies (8). There are few data regarding preventive chemoprophylaxis in the ICU; however, Oliveira et al recommended routine chemoprophylaxis with neuraminidase inhibitors for all adult ICU patients on a daily basis from the start of an outbreak (conrmed case in an ICU patient) until approximately 1 wk after the end of the outbreak (9). Current CDC recommendations suggest antiviral chemoprophylaxis with neuraminidase inhibitors should be reserved for those patients with likely nH1N1 exposure who are at high risk for complications (5). In accordance with this, we have adopted a strategy of heightened surveillance to identify symptomatic patients, early isolation, and treatment of patients with unexplained fever or other symptoms (before diagnostic testing results). However, we have not used chemoprophylaxis routinely for asymptomatic, unexposed ICU patients during either seasonal inuenza outbreaks or the present pandemic. This practice is based on our prior experience with seasonal inuenza disease. Of note, both the CDC recommendations and our hospital and PICU policies regarding the diagnosis, isolation, and management of patients infected with nH1N1 inuenza have evolved throughout the pandemic and are expected to continue to change as new data become apparent.

Effect of Early Antiviral Treatment

Aoki et al demonstrated that early treatment with neuraminidase inhibitor therapy has the greatest effect on symptom duration and severity in a healthy population. Although 48 hrs is the most frequently recPediatr Crit Care Med 2010 Vol. 11, No. 2

ommended interval for therapy, the authors demonstrated that treatment as early as 12 hrs after symptom onset had greater effects than treatment at 48 hrs (10). Eighty-ve percent of our patients were treated; all those treated received the neuraminidase inhibitor oseltamivir, which has demonstrated efcacy in decreasing viral shedding and the duration of mild symptoms in uncomplicated seasonal inuenza (11). Reasons for failure to treat included signicant delay in diagnosis with spontaneous resolution of symptoms. However, patient 1 illustrates the risks of delayed treatment, especially in patients with signicant comorbidities. Patient outcomes (Table 4) are divided into subgroups of early treatment (oseltamivir administered within 48 hrs of symptom onset) and late treatment (oseltamivir administered after 48 hrs of symptoms). The reasons for delayed treatment include delayed presentation and delayed diagnosis. Although not statistically signicant, we are limited in our conclusions because we had a small number of patients. Still, we did note trends toward shorter ICU stays, shorter duration of mechanical ventilation, and shorter interval between oseltamivir and extubation (as a surrogate for clinical improvement) in the early treatment group. We report these ndings because there is a paucity of data about the use of antiviral agents for severe inuenza disease in critically ill patients, and there are even fewer data in children. Our experience supports the CDC advisory of immediate, presumptive treatment of critically ill children with a history suggestive of nH1N1 inuenza disease (regardless of duration of symptoms) because the risk/benet ratio for these patients is likely in favor of therapy. DFA has a high false-negative rate and denitive culture diagnosis takes several days. Although widespread resistance to neuraminidase inhibitors among seasonal inuenza A has occurred (including rare reports of nH1N1 isolates) (12), the nH1N1 inuenza virus seems to still be largely sensitive to oseltamivir (13). Whitley et al suggested that oral dosing to children 12 months results in costeffective reduction of disease burden and viral shedding (14). Oseltamivir is only approved for use in patients 12 months of age, but during this epidemic the U.S. Food and Drug Administration approved an Emergency Use Authorization for treatment of inuenza infection in patients 12 months old. Oseltamivir is not available in a parenteral formulation; we were able to treat four of our patients

(including patients 1 and 3) via nasogastric or gastrostomy tube. This practice is supported by a pharmacokinetic study of nasogastric administration of oseltamivir to adults demonstrating good absorption and extensive metabolism to the active metabolite, oseltamivir carboxylate, even in critically ill patients with severe inuenza (15). The Food and Drug Administration recently approved intravenous peramivir for compassionate use, although there are very limited data for its use in pediatric patients. The CDC has recommended peramivir in unresponsive or deteriorating patients or in patients unable or unlikely to absorb oseltamivir. Intravenous peramivir can be obtained through the CDC at http://emergency.cdc.gov 1N1antivirals.

Bacterial Superinfection
A key component of severe inuenza management involves surveillance for and early treatment of bacterial superinfection. Reed et al found that, among children hospitalized with seasonal inuenza disease, 15% had culture-proven bacterial infection (16). The most common organism among those cases was Staphylococcus aureus (including methicillin-resistance in 40% of S. aureus isolates). Patients with bacterial infection were also more likely to require critical care and had a higher patient fatality than other children with inuenza. In our series, 23% of our nH1N1 inuenza-infected patients developed clinical and radiographic evidence of bacterial superinfection, although none of our patients had positive bacterial respiratory cultures (3). Enhanced morbidity and mortality with inuenza-related bacterial infection may be due to increased viral replication and pathogenicity caused by proteolytic activation of hemagglutinin (17). Seasonal inuenza A has also been reported to downregulate neutrophil function (18), which would theoretically provide a more hospitable milieu for bacterial infection. Critically ill children with nH1N1 inuenza disease deserve extreme vigilance for bacterial superinfection.

Survival
All 13 patients in this case series survived until discharge. This nding contrasts with a report by Li et al revealing a mortality rate of 18.5% in a cohort of more severely compromised critically ill adult patients (Acute Physiology and
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Chronic Health Evaluation III scores of 82 20 in nonsurvivors) with seasonal inuenza A infection (19). The comparison between our data and those by Li et al should be interpreted cautiously because of the younger age group, the early stage of a new pandemic, and the less severe illness in our cohort. None of our patients required renal replacement therapy or extracorporeal support. Regardless, we report that, in this series of 13 children in our PICU, 12 of whom had known highrisk conditions for severe inuenza disease, mortality was 0%.

nitive diagnostic testing is available. Additional epidemiologic studies in children are desperately needed to guide surveillance practices and infection prevention and control strategies for emerging pathogens, such as nH1N1 inuenza

8.

9.

ACKNOWLEDGMENTS
We thank Alicia Budd in Hospital Epidemiology and Infection Control at The Johns Hopkins Hospital whose efforts tracking the patients of nH1N1 during the emerging pandemic were invaluable in the identication of patients for this manuscript.
10.

11.

CONCLUSIONS
This series illustrates the presentation of critical nH1N1 inuenza disease in the PICU. The pediatric intensivist must be prepared for hemodynamic instability and highly individualized ventilator management, depending on whether bronchospasm or alveolar consolidation predominates. Signicant sedation and even neuromuscular blockade may be necessary to manage paroxysms of severe coughing. All patients including those presenting with mild-moderate cardiovascular, respiratory, and hematologic dysfunction as well as bacterial superinfection survived. The duration of critical illness was not different between early and late treatment groups. Whether this is reective of sample size or indicative of the importance of therapeutic intervention at any time early during infection in critically ill patients is unclear. The effect of early antiviral therapy on critically ill pediatric patients with inuenza infection (nH1N1 or seasonal) is an area for future larger studies. In the meantime, practitioners are advised to have a high index of suspicion and to consider presumptive treatment of all critically ill patients, regardless of duration of symptoms, until de-

REFERENCES
1. Fraser C, Donnelly CA, Cauchemez S, et al: Pandemic potential of a strain of inuenza A (H1N1): Early ndings. Science 2009; 324: 15571561 2. Novel Swine-Origin Inuenza A (H1N1) Virus Investigation Team, Dawood FS, et al: Emergence of a novel swine-origin inuenza A (H1N1) virus in humans. N Engl J Med 2009; 360:26052615 3. Langley JM, Bradley JS: Dening pneumonia in critically ill infants and children. Pediatr Crit Care Med 2005; 6(3 Suppl):S9 S13 4. Pollack MM, Patel KM, Ruttimann UE: PRISM III: An updated Pediatric Risk of Mortality score. Crit Care Med 1996; 24:743752 5. Centers for Disease Control and Prevention (CDC): Updated interim recommendations for the use of antiviral medications in the treatment and prevention of inuenza for the 2009 2010 season. Available at http://www.cdc. gov/h1n1u/recommendations.htm. Accessed October 21, 2009 6. Panning M, Eickmann M, Landt O, et al: Detection of inuenza A(H1N1)v virus by realtime RT-PCR. Euro Surveill 2009; 14:pii 19329.Availableathttp://www.eurosurveillance. org/ViewArticle.aspx?ArticleId 19329. Accessed October 21, 2009 7. Centers for Disease Control and Prevention (CDC): Evaluation of rapid inuenza diag-

12.

13.

14.

15.

16.

17.

18.

19.

nostic tests for detection of novel inuenza A (H1N1) virusUnited States, 2009. MMWR Morb Mortal Wkly Rep 2009; 58:826 829 Aziz AM: Pandemic inuenza: Implications for infection control in hospital. Br J Nurs 2008; 17:1020 1026 Oliveira EC, Lee B, Colice GL: Inuenza in the intensive care unit. J Intensive Care Med 2003; 18:80 91 Aoki FY, Macleod MD, Paggiaro P, et al: Early administration of oral oseltamivir increases the benets of inuenza treatment. J Antimicrob Chemother 2003; 51:123129 Hayden FG, Treanor JJ, Fritz RS, et al: Use of the oral neuraminidase inhibitor oseltamivir in experimental human inuenza: randomized controlled trials for prevention and treatment. JAMA 1999; 282:1240 1246 Hayden F: Developing new antiviral agents for inuenza treatment: What does the future hold? Clin Infect Dis 2009; 48(Suppl 1):S3S13 Centers for Disease Control and Prevention (CDC): Update: Drug susceptibility of swineorigin inuenza A (H1N1) viruses. MMWR Morb Mortal Wkly Rep 2009; 58:433 435 Whitley RJ: The role of oseltamivir in the treatment and prevention of inuenza in children. Expert Opin Drug Metab Toxicol 2007; 3:755767 Taylor WR, Thinh BN, Anh GT, et al: Oseltamivir is adequately absorbed following nasogastric administration to adult patients with severe H5N1 inuenza. PLoS One 2008; 3:e3410 Reed C, Kallen AJ, Patton M, et al: Infection with community-onset Staphylococcus aureus and inuenza virus in hospitalized children. Pediatr Infect Dis J 2009; 28:572576 Scheiblauer H, Reinacher M, Tashiro M, et al: Interactions between bacteria and inuenza A virus in the development of inuenza pneumonia. J Infect Dis 1992; 166:783791 Pang G, Clancy R, Cong M, et al: Inuenza virus inhibits lysozyme secretion by sputum neutrophils in subjects with chronic bronchial sepsis. Am J Respir Crit Care Med 2000; 161:718 722 Li G, Yilmaz M, Kojicic M, et al: Outcome of critically ill patients with inuenza virus infection. J Clin Virol 2009; 46:275278

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