Abstract
Background
Knowledge about the incidence, clinical course and impact of respiratory viral infections in children with acute lymphoblastic leukemia (ALL) is limited.
Methods
A retrospective cohort of patients with newly diagnosed ALL on Total Therapy XVI protocol at St Jude Children’s Research Hospital between 2007 and 2011 was evaluated.
Results
Of 223 children, 95 (43%) developed 133 episodes of viral acute respiratory illness (ARI) (incidence = 1.1/1,000 patient-days). ARI without viral etiology was identified in 65 (29%) patients and no ARI in 63 (28%). There were no significant associations between race, gender, age, or ALL risk group and development of ARI. Children receiving induction chemotherapy were at the highest risk for viral ARI (incidence, 2.3 per 1,000 patient-days). Influenza virus was the most common virus (38%) followed by respiratory syncytial virus (RSV) (33%). Of 133 episodes of viral ARI, 61% of patients were hospitalized, 26% suffered a complicated course, 80% had their chemotherapy delayed, and 0.7% died. Twenty-four (18%) patients developed viral lower respiratory tract infection (LRTI); of which 5 (21%) had complications. Patients with viral LRTI had significantly lower nadir absolute lymphocyte count, were sicker at presentation, and were more likely to have RSV, to be hospitalized, and to have their chemotherapy delayed for longer time compared to those with viral URTI.
Conclusion
Despite the low incidence of viral ARI in children with ALL, the associated morbidity, mortality, and delay in chemotherapy remain clinically significant. Viral LRTI was particularly associated with high morbidity requiring intensive care level support.
Keywords: Respiratory virus, infection, pediatric, immunocompromised, leukemia
INTRODUCTION
Over the past decades, major advances have been made in childhood acute lymphoblastic leukemia (ALL) therapy resulting in 92% 10-year survival rate1. However, infectious complications remain a significant cause of morbidity and mortality in children with ALL2. Of particular importance are respiratory viral infections that are characterized by a wide spectrum of manifestations ranging from mild cold symptoms to progression to lower respiratory tract infection, and increased hospitalization rates3–5. In a prospective multicenter study, 44% of febrile episodes in children with leukemia were attributed to respiratory viral infections3. However, most of the existing knowledge about the clinical course of respiratory viral infections in immunocompromised patients has been derived from studies that collectively evaluated adult patients with cancer or transplant recipients. Studies describing the epidemiology of respiratory viral infections in children with ALL are limited2,3. In addition, the incidence of respiratory infections of any etiology has not been documented in children with ALL.
In this study, a retrospective cohort of children with newly diagnosed ALL treated in a single contemporary protocol was evaluated for the epidemiology, incidence, clinical course, and impact of respiratory viral infections.
PATIENTS AND METHODS
Study Design and Patients
All patients (≤ 18 year old) were enrolled on ALL treatment protocol (Total Therapy XVI) at St. Jude Children’s Research Hospital (SJCRH) in Memphis, Tennessee between October 2007 and May 2011. The ALL treatment regimen and risk classification of Total Therapy XVI6 were completed using consistent criteria based on the previously published Total Therapy XV7. Therapy consisted of a 6-week remission induction, 8-week consolidation, and 120-week continuation phase that included two 3-week periods of more intensive chemotherapy (re-induction I and re-induction II). The electronic database for Total Therapy XVI cohort and medical records were reviewed for demographic data, clinical course and outcome, and results of respiratory viral testing that was driven by clinical care of patients with acute respiratory symptoms.
Respiratory specimens included nasopharyngeal swab or wash, tracheal aspirate, and/or bronchoalveolar lavage (BAL). Respiratory viral testing consisted of viral culture, direct fluorescent antibody (DFA) immunoassay, and polymerase chain reaction (PCR) that detected influenza A and B, parainfluenza virus, human metapneumovirus (hMPV), adenovirus, and respiratory syncytial virus (RSV). The method for diagnostic testing has not changed during the study period.
SJCRH is a 64 inpatient bed referral center for children with cancer and other catastrophic diseases of childhood. This study was approved by the Institutional Review Board at SJCRH.
Definitions
Patients are classified into one of three ALL risk groups (low-, standard-, or high-risk) based on presenting age, leukocyte count, central nervous system or testicular leukemia, immunophenotype, cytogenetics and molecular genetics, DNA index, and response to therapy7. Acute respiratory illness (ARI) was classified as either upper respiratory tract infection (URTI) or lower respiratory tract infection (LRTI). Patients were classified to have URTI if they had a new onset of any of the following symptoms: rhinorrhea, nasal congestion, sore throat, or cough, with or without fever, with normal chest physical and radiological examination. Patients with signs or symptoms of URTI and new abnormal pulmonary findings on chest physical examination or imaging were classified as having LRTIs. Secondary pneumonia suspected or proven to be of bacterial or fungal etiology was defined based on clinical and radiological criteria with or without bacterial or fungal organisms identified in respiratory specimens. Clinical criteria include new onset or worsening of cough, dyspnea, tachypnea, or hypoxia; with radiological findings consistent with bacterial or fungal pneumonia such as consolidation, cavitation, or pneumatocele. Fever was defined as a single oral temperature of ≥38.3°C or an oral temperature of ≥38.0°C that persists for over 1 hour. Neutropenia was defined as an absolute neutrophil count (ANC) ≤ 500 cells/mm3, lymphopenia as an absolute lymphocyte count (ALC) ≤ 300 cells/mm3, and monocytopenia as an absolute monocyte count (AMC) ≤ 200 cells/mm3. Clinical complications included secondary infections, altered mental status, arrhythmia or electrocardiographic changes, bleeding requiring transfusion, congestive heart failure, disseminated intravascular coagulation, hypotension, intensive care unit (ICU) admission, respiratory failure, renal failure, and other complications judged clinically significant by the investigator. Because alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations are common in ALL patients receiving chemotherapy, for the purpose of this study, AST and/or ALT elevations at more than twice the upper normal limit that are not temporally related to chemotherapy were considered a complication of viral infection. Patient-days were defined as the number of days contributed by the cohort from the date of ALL diagnosis to any of the following dates, whichever occurred first: completion of continuation therapy, death, relapse and removal off Total Therapy XVI protocol, or end date of the current study.
Statistical Analysis
Groups were compared using Fisher’s Exact or Chi-square tests for categorical data, or Wilcoxon rank-sum test or Student’s t test for continuous data. All tests were 2-tailed and a P value of <0.05 was considered as statistically significant. Incidence density of ARI was reported per 1,000 patient-days. SAS version 9.3 (SAS institute, Cary, NC) was used.
RESULTS
Incidence of ARI with and without Documented Viral Etiology
A cohort of 223 patients with newly diagnosed ALL enrolled on Total Therapy XVI and contributed a total of 125,773 patient-days. A total of 133 episodes of ARI with viral etiology occurred in 95 (43%) patients (Table 1). Of those, 64 patients had one episode, 24 patients had 2 episodes and 7 patients had 3 episodes. The incidence density of ARI with viral etiology is 1.1 per 1,000 patient-days (Table 2). Sixty-five (29%) patients had 136 episodes of ARI without viral etiology, resulting in an incidence of 1.1 per 1,000 patient-days (Table 1). Sixty-three (28%) patients did not have any ARI during the study period (Table 1).
Table 1.
Clinical Characteristics of Children with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL) with and without Development of Acute Respiratory Illness (ARI) during Chemotherapy
| Characteristics | Total n=223 |
No ARI n=63 (28%) |
ARI with Viral Etiology n=95 (43%) |
ARI without Viral Etiology n=65 (29%) |
P-value* |
|---|---|---|---|---|---|
| Race | |||||
| White | 170 (76) | 46 (73) | 73 (77) | 51 (78) | 0.61 |
| Black | 34 (15) | 13 (21) | 12 (13) | 9 (14) | |
| Other | 19 (9) | 4 (6) | 10 (10) | 5 (8) | |
| Male gender | 127 (57) | 39 (62) | 50 (53) | 38 (59) | 0.49 |
| ALL Therapy Risk Level | |||||
| Low | 84 (38) | 20 (32) | 42 (44) | 22 (34) | 0.57 |
| Standard | 121 (54) | 36 (57) | 48 (50) | 37 (58) | |
| High | 18 (8) | 7 (11) | 6 (6) | 5 (8) | |
| Age at ALL diagnosis in years | |||||
| 0 – <2 | 18 (8) | 2 (3) | 12 (13) | 4 (6) | 0.14 |
| 2 – <5 | 85 (38) | 23 (37) | 40 (42) | 22 (34) | |
| 5 – <10 | 60 (27) | 17 (27) | 20 (21) | 23 (35) | |
| ≥10 | 60 (27) | 21 (33) | 23 (24) | 16 (25) |
Data are n (%)
Pearson’s Chi-Square Test
ALL, acute lymphoblastic leukemia; ARI, acute respiratory illness
Table 2.
Incidence of Acute Respiratory Illness (ARI) with Viral Etiology in each Chemotherapy Phase per 1,000 patient-days
| Treatment Phase | Number of ARI with Viral Etiology | Patient-days | Incidence of ARI with Viral Etiology per 1,000 patient-days |
|---|---|---|---|
|
| |||
| Before Initiation of Chemotherapy | 4 | . | . |
|
| |||
| Remission Induction | 11 | 4,854 | 2.3 |
|
|
|||
| Low Risk | 4 | 1,826 | 2.2 |
|
|
|||
| Standard/High Risk | 3,028 | 2.3 | |
|
| |||
| Consolidation | 12 | 18,171 | 0.7 |
|
|
|||
| Low Risk | 5 | 6,796 | 0.7 |
|
|
|||
| Standard/High Risk | 7 | 11,375 | 0.6 |
|
| |||
| Continuation Week1 to Re-induction II | 25 | 25,985 | 1.0 |
|
|
|||
| Low Risk | 13 | 9,180 | 1.4 |
|
|
|||
| Standard/High Risk | 12 | 16,805 | 0.7 |
|
| |||
| Continuation Post Re-induction II | 81 | 77,206 | 1.1 |
|
|
|||
| Low Risk | 34 | 31,645 | 1.1 |
|
|
|||
| Standard/High Risk | 47 | 45,561 | 1.0 |
|
| |||
| Overall | 133 | 125,773 | 1.1 |
|
|
|||
| Low Risk | 59 | 49,116 | 1.2 |
|
|
|||
| Standard/High Risk | 74 | 76,657 | 1.0 |
Risk factors for ARI with and without Documented Viral Etiology
Children with newly diagnosed ALL were mostly white male and had standard risk ALL. There were no significant difference between children who developed ARI with and without viral etiology and those who did not develop any ARI during the study period (Table 1). Patients who developed ARI with viral etiology tended to be younger (<5 years, 55%) compared to those with ARI without viral etiology (40%) or to those who did not have any ARI (40%, p=0.19). Although most (62%) of the 133 episodes of ARI with viral etiology occurred during continuation, which is the longest chemotherapy phase, patients receiving remission induction chemotherapy were at the highest risk for viral respiratory infections with an incidence of 2.3 per 1,000 patient-days (Table 2).
Epidemiology of ARI with Documented Viral Etiology
Episodes of ARI with viral etiology were proportionately distributed among the years from 2007 to 2011 (Figure 1). The highest number of influenza virus, detected in 20 ARI with viral etiology, was recorded in 2009, while that detected in 2010 and 2011 were 15 and 14 episodes, respectively.
Figure 1. Distribution of Acute Respiratory Illness (ARI) with Viral Etiology per Year.
Because prior to October 2007 children received therapy per previous regimen, only one ARI with viral etiology was identified in 2007 and 12 in 2008 as part of this study. In order to obtain an accurate estimate of the frequency of respiratory viral infections each year, additional 75 episodes of ARI with viral etiology that occurred in children with ALL continuing therapy per the previous Total Therapy XV protocol, and thus not enrolled in this study, were also included in Figure 1.
A total of 139 respiratory viruses were identified in 133 episodes of ARI with viral etiology. Co-infection with 2 or more viruses occurred in 6 episodes. Of the 133 viral ARI, 84 (63%) occurred between December and March (Figure 2). Influenza virus was the most frequent virus, identified in 51 (38%) episodes, followed by RSV in 45 (34%) episodes (Figure 2). Respiratory viral infections with influenza and RSV showed seasonal distribution with a peak in February (Figure 2) as seen in previous reports8.
Figure 2.
Distribution of the Identified Respiratory Viruses per Month
Description of the Clinical Course and Outcomes of ARI with Documented Viral Etiology
Of the 133 episodes of ARI with viral etiology, patients developed LRTI in 24 (18%) episodes (Table 3). Patients who developed LRTI with viral etiology had significantly lower nadir ALC during their illness with a median ALC of 165 (range 0–989) cells/mm3 compared to a median ALC of 368 (range 0–1,800) cells/mm3 in those who had URTI with viral etiology (p=0.01). Also, patients with viral LRTI were more likely to appear clinically ill and develop higher degree of fever for longer duration than those with URTI (p < 0.05, Table 3).
Table 3.
Comparison of the Clinical Course and Outcomes of Upper versus Lower Respiratory Tract Infection in Children with Acute Lymphoblastic Leukemia and Acute Respiratory Illness (ARI) with Viral Etiology
| Characteristics | Total ARI with Viral Etiology N=133 |
Upper Respiratory Tract Infection N=109 (82%) |
Lower Respiratory Tract Infection N=24 (18%) |
P-value |
|---|---|---|---|---|
|
Demographics and Potential Risk Factors | ||||
| Age in years at onset of ARI, median (range) | 5.4 (1.0–20.6) | 5.5 (1.2–20.4) | 5.0 (1.0–20.6) | 0.9 |
|
| ||||
| Male gender | 69 (52) | 57 (52) | 12 (50) | 0.9 |
|
| ||||
| G-CSF at presentation | 1 (0.7) | 1 (0.9) | 0 | NA |
|
| ||||
| Days since previous chemotherapy, median (range) | 2 (2–23) | 2 (2–23) | 2 (2–22) | 0.4 |
|
| ||||
| Reported exposure to respiratory infection | 34 (25) | 29 (26) | 5 (21) | 0.8 |
|
| ||||
| Palivizumab or IVIG immune prophylaxis# | 12 (9) | 9 (8) | 3 (13) | 0.5 |
|
| ||||
| Seasonal Influenza vaccination$ | 52 (39) | 39 (36) | 13 (54) | 0.2 |
|
| ||||
| 2009 pandemic H1N1 monovalent vaccine* | 19 (14) | 17 (16) | 2 (8) | 0.4 |
|
| ||||
| ANC at onset of ARI, median (range) | 900 (0–8,500) | 850 (0–8,000) | 1200 (0–8,500) | 0.6 |
|
| ||||
| ALC at onset of ARI, median (range) | 480 (30–10,810) | 474 (86–10,810) | 483 (30–3,570) | 0.4 |
|
| ||||
| AMC at onset of ARI, median (range) | 276 (0–4,400) | 276 (0–4,400) | 300 (0–810) | 0.5 |
|
| ||||
| Nadir ANC during ARI, median (range) | 266 (0–2,200) | 300 (0–2,200) | 200 (0–2,000) | 1.0 |
|
| ||||
| Nadir ALC during ARI, median (range) | 342 (0–1,800) | 368 (0–1,800) | 165 (0–989) | 0.01 |
|
| ||||
| Neutropenia (ANC ≤500 cells/mm3) | 45 (34) | 36 (33) | 9 (38) | 0.6 |
|
| ||||
| Lymphopenia (ALC ≤300 cells/mm3) | 33 (25) | 25 (23) | 8 (33) | 0.3 |
|
| ||||
| Monocytopenia (AMC ≤200 cells/mm3) | 53 (40) | 42 (38) | 11 (46) | 0.5 |
|
| ||||
| Days of neutropenia before onset of ARI, median (range) | 2 (0–19) | 2 (0–19) | 8.5 (0–15) | 0.4 |
|
| ||||
| Days of lymphopenia before onset of ARI, median (range) | 2 (0–50) | 2 (0–50) | 1.5 (1–8) | 0.8 |
|
| ||||
| Days of monocytopenia before onset of ARI, median (range) | 8 (0–57) | 5 (0–57) | 8 (2–14) | 0.3 |
|
| ||||
| Detected Respiratory virus | ||||
| Influenza virus | 48 (36) | 44 (40) | 4 (17) | 0.03 |
| Respiratory syncytial virus | 41 (31) | 27 (25) | 14 (58) | 0.003 |
| Parainfluenza virus | 24 (18) | 22 (20) | 2 (8) | 0.4 |
| Human metapneumovirus | 13 (10) | 12 (11) | 1 (4) | 0.5 |
| Human adenovirus | 1 (0.7) | 1 (1) | 0 | 0.5 |
| ≥2 virus co-infection | 6 (5) | 3 (3) | 3 (13) | 0.1 |
|
Clinical Course | ||||
| Clinical Presentation | ||||
| Fever | 115 (86) | 93 (85) | 22 (92) | 0.5 |
| Cough | 125 (94) | 103 (94) | 22 (92) | 0.6 |
| Rhinorrhea | 89 (67) | 77 (71) | 12 (50) | 0.06 |
| Nasal Congestion | 61 (46) | 51 (47) | 10 (42) | 0.8 |
| Sore throat | 10 (7) | 9 (8) | 1 (4) | 0.7 |
| Myalgia | 9 (7) | 6 (5) | 3 (12) | 0.2 |
| Rigors | 6 (5) | 5 (5) | 1 (4) | 1.0 |
| Vomiting | 29 (22) | 22 (20) | 7 (29) | 0.4 |
| Abdominal pain | 9 (7) | 5 (5) | 4 (17) | 0.05 |
| Headache | 18 (14) | 15 (14) | 3 (13) | 1.0 |
|
| ||||
| Sick clinical appearance | 31 (23) | 21 (19) | 10 (42) | 0.01 |
|
| ||||
| Days of fever, median (range) | 3 (1–47) | 3 (1–47) | 4.5 (1–47) | 0.03 |
|
| ||||
| Highest temperature in °C, median (range) | 39.0 (37.7–42.5) | 39.0 (37.7–41.4) | 39.6 (38.0–42.5) | 0.01 |
|
| ||||
| Antiviral therapy | 66 (50) | 50 (46) | 16 (67) | 0.07 |
|
| ||||
| Days of antiviral therapy, median (range) | 5 (1–30) | 5 (1–19) | 5 (1–30) | 0.9 |
|
| ||||
| IVIG therapy | 15 (11) | 10 (9) | 5 (21) | 0.1 |
|
| ||||
| Empiric antibacterial therapy | 115 (87) | 91 (84) | 24 (100) | 0.04 |
|
Outcome | ||||
| Hospitalized for ARI | 81 (61) | 61 (56) | 20 (83) | 0.02 |
|
| ||||
| Any complication | 34 (26) | 21 (19) | 13 (54) | 0.002 |
|
| ||||
| Days to first complication, median (range) | 5 (1–31) | 5 (1–26) | 5 (1–31) | 0.2 |
|
| ||||
| Chemotherapy due during illness | 127 (96) | 103 (95) | 24 (100) | 0.6 |
|
| ||||
| Chemotherapy delayed due to illness | 101 (80) | 80 (73) | 21 (88) | 0.3 |
|
| ||||
| Chemotherapy dose/drugs modified due to illness | 47 (37) | 38 (37) | 9 (37) | 0.8 |
|
| ||||
| Days of chemotherapy delay, median (range) | 8 (1–99) | 8 (1–26) | 14.5 (1–99) | 0.01 |
|
| ||||
| Death during ARI | 1 (0.7) | 0 | 1 (4) | 0.2 |
Data is represented as n (%) unless otherwise stated.
Of the 45 episodes of ARI with detected RSV, 3 (7%) had received anti-RSV immunoprophylaxis compared to 9 (10%) of the 89 episodes of ARI without RSV (p=0.7).
Of the 51 episodes of ARI with detected influenza virus, 15 (29%) had received prior influenza vaccination compared to 37 (45%) of the 83 episodes of ARI without influenza virus (p=0.1).
Of the 39 episodes of ARI with viral etiology that occurred in 2009, 19 (49%) had received monovalent 2009 pandemic H1N1 influenza vaccine.
ARI, acute respiratory illness; G-CSF, granulocyte colony stimulating factor; IVIG, intravenous immunoglobulin; ANC, absolute neutrophil count; ALC, absolute lymphocyte count; AMC, absolute monocyte count
Influenza virus was the only virus detected in 48 (36%) episodes of ARI with viral etiology; the majority (92%) of which were URTI (Table 3). Influenza virus was significantly more likely to be detected in those with URTI (40%) than in those with LRTI (17%, p-value = 0.03). On the other hand, RSV was more likely to be associated with LRTI. RSV was the only virus detected in 41 (31%) episodes of viral ARI; 34% of which were LRTI (Table 3). RSV was significantly more likely to be detected in those with LRTI (58%) than in those with URTI with viral etiology (25%, p-value = 0.003).
Hospitalization
Eighty-one (61%) patients with viral ARI required hospitalization, mostly for management of febrile neutropenia. Children who developed LRTI were significantly more likely to be hospitalized than those with URTI (83% vs. 56%, p = 0.02).
Complications
Thirty four (26%) viral ARI had a complicated clinical course. Of 109 URTI, 21 (19%) patients developed complications including otitis media (9 episodes), sinusitis (2), parotitis (1), pancytopenia (1), and hypoglycemia (1). Pulmonary nodules suggestive of fungal infection were detected on chest CT scans completed for workup of persistent febrile neutropenia in 3 patients, each with RSV, influenza B virus, and parainfluenza virus type 3, respectively. Four other patients presented with hypotension and fever; one with hMPV and Escherichia coli bacteremia, one with RSV and dehydration due to poor oral intake, one with influenza A virus and newly diagnosed ALL, and one with influenza A virus with no alternative etiology for hypotension. All these patients responded to intravenous fluid infusions without vasopressor support or ICU admission.
Patients with viral LRTI were more likely to develop complications than those with URTI (p = 0.002, Table 3). One patient with RSV LRTI developed viral pericarditis and pericardial temponade requiring pericardial window. However, secondary suspected or proven bacterial or fungal infection was the most frequent complication occurring in 12 (50%) patients with viral LRTI. Sinusitis was diagnosed in 2 patients (1 with RSV and 1 with 2009 pandemic H1N1 influenza A virus), acute otitis media in 1 patient with RSV, and presumed bacterial consolidating pneumonia in 11 patients (7 with RSV, 2 with 2009 pandemic H1N1 influenza A virus, 1 with parainfluenza virus type 3 / Pseudomonas aeruginosa bacteremia, and 1 with RSV/influenza B virus co-infection). Of the 11 patients with consolidating pneumonia, 4 developed respiratory failure requiring mechanical ventilation (3 with RSV and 1 with 2009 pandemic H1N1 influenza A virus) while 5 patients required only nasal oxygen support and 2 patients did not require any support. The complicated clinical course of 5 patients with viral LRTI (3 patients with RSV, 1 patient with 2009 pandemic H1N1 influenza A virus, and the one patient with parainfluenza virus type 3 / Pseudomonas aeruginosa bacteremia) further progressed to hemodynamic and multi-organ insufficiency requiring vasopressor support; one of whom (an infant with RSV) received extra-corporeal mechanical oxygenation and died 2 months after onset of infection. ICU admission was required for 6 patients with LRTI with viral etiology. Of the 13 patients with complicated viral LRTI, 8 (62%) were lymphopenic and 9 (69%) neutropenic. Only 2 (22%) of the 9 patients with complicated LRTI with RSV had received immunoprophylaxis with palivizumab; and only 1 of the three patients with complicated LRTI with influenza virus had received prior influenza vaccination.
Impact on Chemotherapy
127 (95%) patients were scheduled for chemotherapy course at the onset of viral ARI (Table 3). There was no significant difference between the proportions of patients who had their chemotherapy delayed or dose modified among those with viral LRTI compared to those with viral URTI. However, patients with viral LRTI had their chemotherapy delayed for significantly longer period of time [median (range) = 14.5 (1–99) days] than those with viral URTI [median (range) = 8 (1–26) days, p = 0.01].
Viral Co-infection
Of the 133 episodes of ARI with viral etiology, patients were identified to be co-infected with ≥ 2 viruses in 6 (5%) episodes (Table 3). Two patients with URTI had RSV and parainfluenza virus type 3 co-infection, and a third one had parainfluenza type 3 and 2009 pandemic H1N1 influenza A. Additional 3 patients with LRTI were identified to be co-infected with: RSV and cytomegalovirus interstitial pneumonitis (1), influenza A and hMPV (1), and RSV and influenza B virus (1). Of the 6 viral co-infection episodes of ARI, only the patient identified to have RSV and influenza B virus LRTI progressed to develop secondary presumed bacterial pneumonia and required nasal oxygen support. However, this patient recovered after a 5 day course of oseltamivir and azithromycin and a 10 day course of vancomycin and cefepime.
Mortality
Infection-related mortality rate was 0.7%. This was an 11 month old girl who received high-dose cytarabine for Re-induction II chemotherapy. She presented with a 3 day history of progressively worsening cough and nasal congestion, and new onset fever and respiratory distress with profound neutropenia and lymphopenia; for which she was hospitalized. She had received palivizumab immunoprophylaxis 10 days prior to illness and 2 doses of seasonal influenza vaccine. Initial evaluation revealed bilateral peri-bronchial thickening and RSV was detected on nasopharyngeal wash specimen by PCR. Aerosolized ribavirin treatment was initiated in addition to oxygen support and broad spectrum antibiotic therapy. However, due to progressive respiratory deterioration and increasing fever, chest x-ray repeated on day 5 of hospitalization showed left lower lobe consolidation pneumonia suggestive of secondary bacterial infection. Her treatment regimen included vancomycin, meropenem, azithromycin, voriconazole, palivizumab and aerosolized ribavirin. On hospital day 28, her condition progressed to respiratory and hemodynamic failure requiring mechanical ventilation, vasopressor followed by extra-corporeal mechanical oxygenation support. She died 2 months after RSV infection onset.
DISCUSSION
Our study is the first to evaluate the incidence, clinical course and outcome of respiratory viral infections in children with newly diagnosed ALL treated on contemporary protocols. Respiratory viruses were detected in 133 episodes of ARI that occurred in less than half (43%) of this cohort over a 31-month period. This accounts for an incidence of 1.1 respiratory viral infections per 1,000 patient-days of ALL therapy, which is lower than the incidence reported in previous studies3,9. In a Finnish prospective study of 51 children with leukemia, Koskenvuo and colleagues detected a respiratory viral etiology in 61 (44%) of 138 febrile episodes and reported an incidence of 0.8 per person-year (equivalent to 2.2/1,000 patient-days) at risk3. A previous study9 published in 1995 reported an incidence of 5.2/1,000 patient-days at risk [95% confidence interval 3.9–7.0]. The decreasing incidence of respiratory viral infections in children with ALL over the past decades parallels advances in anti-viral immune prophylaxis and chemoprophylaxis and increasing rates of vaccination as a protective approach against influenza. However, limitations to the interpretation of our findings should be noted. The retrospective design of the study may limit the detection of the complete spectrum of clinical symptoms. Patients with mild upper respiratory symptoms may not present for medical care and thus are not consistently represented in this data. Furthermore, the PCR assay used at our institution for respiratory virus testing did not detect rhinovirus/enterovirus which is the most common cause of URTI in general and in children with leukemia3. For these two reasons, many of the less serious respiratory viral infections may have gone undetected. However, we believe that this does not have a major impact on the purpose of this study, which is evaluating morbidity, mortality, and chemotherapy delays related to respiratory viral infections in ALL patients. A multiplex PCR assay that also detects rhinovirus/enterovirus was implemented for clinical testing at a later date after the study. We anticipate that implementation of this assay will result in both higher rates of respiratory viral infection as well as higher rates of viral co-infections10.
The majority of the respiratory viral infections in our study were detected in children receiving continuation chemotherapy. However, when adjusting for the duration of each chemotherapy phase, children receiving remission induction chemotherapy were at the highest risk for respiratory viral infection (2.3 per 1,000 patient days). During induction, patients were not only neutropenic but also severely immunosuppressed due to prolonged treatment with glucocorticoids.
We have found that influenza virus was the most frequently detected respiratory virus followed by RSV. Influenza virus was more likely to cause URTI while RSV was more likely to cause LRTI. Of the 6 patients who developed influenza LRTI, 3 had 2009 pandemic H1N1 influenza A virus, and one had RSV and influenza B virus co-infection, while the remaining 2 patients had influenza A virus that was not subtyped. Our institution’s experience with influenza infections in general and severe 2009 pandemic H1N1 influenza A infection in particular have been previously published11,12. Carr and colleagues11 reviewed the clinical course and outcome of 107 episodes of influenza infections in pediatric oncology patients between January 2002 and April 2009, i.e. before emergence of 2009 pandemic H1N1 influenza A virus. In this study, 12 (17%) of 69 children with leukemia or lymphoma were reported to develop LRTI, a percentage that was similar to our findings of 12% that also included 2009 pandemic H1N1 influenza A virus. Our experience with 2009 pandemic H1N1 influenza A infection in children with ALL is not different from other reports in oncology patients12–17. Although the majority of immunocompromised patients with 2009 pandemic H1N1 influenza A virus developed a mild course of URTI, few case reports described severe morbidity and mortality. In our study, there was no death associated with 2009 pandemic H1N1 influenza A infection in children with ALL.
Similar to previous studies18–20, we have found that lymphopenia was a risk factor for development of LRTI after respiratory viral infection. However, not only presence of lymphopenia at the onset of respiratory viral infection, but also, more specifically, the severity of lymphopenia measured as nadir ALC during illness was significantly associated with progression to LRTI. Children with ALL who developed viral LRTI were more severely lymphopenic than those who had viral URTI.
Notably, 61% of children with ALL and viral ARI were hospitalized and 26% suffered a complicated course. In general, children with viral URTI who developed a clinical complication most commonly had secondary infections that resolved without any residual consequences. On the other hand, more than half of children who had viral LRTI suffered a complicated clinical course which was more severe than that in children with viral URTI. Secondary bacterial or fungal pulmonary infection was the most common complication, occurring in those with RSV (7), 2009 pandemic H1N1 influenza A (2), and RSV-influenza B co-infection (1) and progressing to multi-organ failure and fatal outcome in one patient. The complicated viral LRTI described in our study was in agreement with previous studies that evaluated the severity of RSV- and influenza-related clinical course in immunocompromised children with cancer12,16–18. It is important to note that despite the seemingly high rate of complications, the mortality rate was 0.7% which is at the lower end of the pediatric fever and neutropenia related mortality range reported as 0.5–6.6%21,22.
In addition to hospitalization and complications, ARI with viral etiology have markedly impacted the chemotherapy course in children with ALL. Majority of those who were scheduled to receive chemotherapy had it delayed for a median of 8 days (range, 1–99 days) and longer than 3 months in children with complicated viral LRTI. It would be important to evaluate the relationship between ALL outcomes at the end of therapy and infection-related chemotherapy delays once the follow-up of the entire cohort of ALL patients on Total Therapy XVI is complete.
In conclusion, despite current advances in ALL cure rates, molecular diagnostic techniques, anti-viral therapies, and active and passive immune prevention approaches, respiratory viral infections remain a significant burden in children with ALL.
Acknowledgments
The authors would like to acknowledge Judy Glenn, Emily Baum and Melissa Shenep for data abstraction and Kris Branum for regulatory support.
Research Support: This work was supported by a National Institutes of Health Grant CA21765 and the American Lebanese Syrian Associated Charities (ALSAC).
Footnotes
Disclaimers: All authors report no conflict of interest.
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