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Original Studies

Respiratory Viral Infections in Children With Leukemia

Koskenvuo, Minna MD*; Möttönen, Merja MD†; Rahiala, Jaana MD‡; Saarinen-Pihkala, Ulla M. MD‡; Riikonen, Pekka MD§; Waris, Matti PhD; Ziegler, Thedi PhD∥; Uhari, Matti MD†; Salmi, Toivo T. MD*; Ruuskanen, Olli MD*

Author Information

From the *Department of Pediatrics, Turku University Hospital, Turku; †Department of Pediatrics, Oulu University Hospital, Oulu; ‡Hospital of Children and Adolescents, University of Helsinki, Helsinki; §Department of Pediatrics, Kuopio University Hospital, Kuopio; ¶Department of Virology, Turku University, Turku; and ∥National Public Health Institute, Helsinki, Helsinki, Finland.

Accepted for publication April 9, 2008.

Supported by The Turku University Hospital Foundation, The Finnish Cancer Organizations, The Foundation of Emil Aaltonen, The Finnish Pediatric Research Foundation, and the Foundation of Virologic Research.

Address for correspondence: Minna Koskenvuo, Department of Pediatrics, Immunology and Transplantation Biology Division, Stanford University, CCSR Building, Room 2100, 300 Pasteur Drive, Palo Alto, CA 94305-5164. E-mail: [email protected]/[email protected].

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The Pediatric Infectious Disease Journal: November 2008 - Volume 27 - Issue 11 - p 974-980
doi: 10.1097/INF.0b013e31817b0799

Abstract

Febrile infection is the most common complication of intensive cancer treatment.1 Bacterial infections are always considered as possible causative agents and empiric antibiotics are used routinely for management in clinical practice. On the other hand, community respiratory viruses are the most common cause of febrile infections in children, and they are a potential cause of febrile episodes also in children receiving anticancer treatment. Previous reports from the 1990s found respiratory viral infections in one-third of febrile periods in children with cancer.2,3 Respiratory syncytial virus (RSV), rhinovirus, parainfluenza viruses, and adenovirus were the most frequently found viruses.2–4 Virus culture and virus antigen detection were used in those studies. With the development of polymerase chain reaction (PCR) techniques, the frequency of respiratory viruses in adults with hematologic malignancies has become evident.5–9 In addition, new respiratory viruses have been identified as causative agents of respiratory disease in immunocompromised subjects.10,11 In children with cancer, only 1 study has used modern sensitive techniques for the search for respiratory viruses as a cause of febrile episodes.12

We conducted a 5-year prospective, multicenter survey of respiratory viruses in febrile children with leukemia. Twelve respiratory viruses were searched for, using virus culture, virus antigen detection, and PCR techniques.

PATIENTS AND METHODS

Patients

The survey was carried out between April 1, 2000 and October 31, 2005 at 4 Finnish university hospitals, including 51 children with acute leukemia (Fig. 1, https://links.lww.com/A530). Table 1 shows the characteristics of the study population. The majority (42/51) of the children were followed from the beginning to completion of the chemotherapy regimen. The mean follow-up time was 1.5 years (range, 0.1–2.5 years; SD 0.6). None of the patients had Down's syndrome. Two children with high-risk acute myeloid leukemia (AML) and 5 with high-risk acute lymphoblastic leukemia (ALL) underwent bone marrow transplantation during the study period, and their follow-up was completed on the day of transplantation. The children were treated according to protocols common to all Nordic countries (NOPHO).13

T1-5
TABLE 1:
Characteristics of the Study Population

We studied 156 febrile episodes during the study period. Fever was defined as an axillary temperature ≥38.0°C, and the interval between separate febrile episodes had to be ≥7 days. In 18 episodes, no virologic samples were taken and 138 fever periods were included in the study (Fig. 2). In all these cases, a blood culture was also taken, with findings reported separately.14 A febrile episode was considered to be nosocomial if fever arose 48 hours after admission. Otherwise, the febrile episode was considered to be community-acquired. The total white blood cell count, absolute neutrophil and lymphocyte counts, and serum C-reactive protein (CRP) levels were recorded during the first febrile day.

F2-5
FIGURE 2.:
The number of episodes in virologic studies, and the clinical features of the febrile episodes with evidence of respiratory viruses.

The studies were approved by the Ethics Committees of Turku, Oulu, Kuopio, and Helsinki Universities. Written informed consent was obtained from the patients (when possible) and from their parents.

Virologic Methods

Respiratory Viral Studies.

A nasal swab sample was obtained by inserting a sterile cotton swab (Applimed SA, Switzerland) to a depth of 2–4 cm into the nostril and retracting it by rotating movements against nasal mucosa. The swab was then inserted into a vial containing viral transport medium (5% tryptose phosphate broth, 0.5% bovine serum albumin, and antibiotics in phosphate-buffered saline).15 The specimens were transported to the laboratory on the same day at room temperature for viral analysis. The specimens from other than the Turku University Hospital were also stored and mailed at room temperature to the Department of Virology, Turku University, within 2 days of collecting the swab samples.

For virus culture, the Ohio strain of HeLa cells and human foreskin fibroblasts were used using standard, well-accepted methods.3 Antigens for RSV; adenovirus; parainfluenza virus types 1, 2, and 3; and influenza A and B viruses were detected using a time-resolved fluoroimmunoassay with monoclonal antibodies.3 Reverse transcription (RT)-PCR was used to detect enteroviruses and rhinovirus, coronavirus types OC43 and 229E, and human metapneumovirus (hMPV), as described previously.16–19 Nucleic acids for RT-PCR were isolated from the nasal swab samples with a commercial kit (High Pure Viral Nucleic Acid Kit, Roche Diagnostics, Mannheim, Germany) according to the manufacture's instructions. The details of the PCR assay for detecting human bocavirus (HBoV) has been reported by Allander et al previously.20 HBoV and hMPV were analyzed retrospectively in the nasal swabs stored at −70°C. Viruses were not routinely sequenced by PCR during or after the study. A case was defined as virus positive if at least one of the tests used was positive for virus.

Statistical Analysis

The results are given as means ± SD, unless stated otherwise. The significance of difference in continuous variables between 2 groups was tested using Student t tests. The number of febrile episodes was calculated per person year at risk (PYR) (Fig. 1, https://links.lww.com/A530).

RESULTS

Respiratory Viruses

Respiratory virus was detected in 61 of 138 (59%) febrile episodes, accounting for an incidence of 0.8 (range, 0–4.0; SD 1.6) per PYR during the treatment of leukemia (Fig. 2). Rhinovirus (22%), RSV (11%), HBoV (5%), and influenza A virus (4%) were the most common viruses found (Table 2). In 9% of the cases, more than one virus was detected, with rhinovirus (n = 11) and RSV (n = 7) as the most common viruses in dual viral infections (Table 2). Of 61 febrile episodes with evidence of respiratory viruses, 8 (13%) were bacterial blood culture positive14 (Fig. 2). All viral findings were based on nasal swab samples (Table 2). PCR detected respiratory virus in 41 of 61 (67%) virus-positive nasal swab samples. It was especially sensitive for picornaviruses (4 cases found by culture compared with 31 by PCR). Rhinoviruses were found throughout the year, but the highest incidences occurred during the fall and spring months. RSV occurred in odd-numbered years during the spring and fall months, which is typical of Finland.21 Influenza viruses were found during the winter months in well-described epidemics.

T2-5
TABLE 2:
The Occurrence of Respiratory Viruses in 138 Febrile Episodes of 51 Children With Leukemia

Follow-up nasal swab samples were taken during 27 febrile episodes within 1–11 days of the primary positive sample, and in 23 cases the test had changed to virus-negative. Three children remained rhinovirus positive and 1 child RSV positive. One child remained rhinovirus positive in 4 samples for 3 weeks. In 9 patients, 2 consecutive febrile episodes were associated with the same virus in 12 pairs (RSV, 6 pairs; rhinovirus, 3 pairs; enterovirus, 2 pairs; influenza A, 1 pair). The intervals between these consecutive episodes varied from 1 week to 3 months (mean, 5.8 weeks; SD 5.4). One child was rhinovirus positive in 3 consecutive febrile episodes during 4 months, and 1 child was HBoV positive with varying copy numbers in 5 consecutive episodes for 6 months.22 One child had 6 rhinovirus positive samples between October 2000 and April 2001, and according to the PCR melting curve analysis and hybridization assay results, he was sequentially infected with at least 3 different rhinovirus types. First 2 samples were 1 rhinovirus type, next 3 samples were another type, and the last sample was still another type.23 The time interval between 2 samples with the same rhinovirus types varied from 1 week to 3 months.

Sole respiratory viral infections tended to be associated more often with lymphopenia (lymphocytes <1.4 × 109/L) than with normal lymphocyte counts (41/116, 35% versus 3/22, 19%), but the difference was not statistically significant (P = 0.09). All children with respiratory symptoms and with one or more virus detections positive were lymphopenic. No association was seen between sole viral infections and neutropenia (neutrophils <1.0 × 109/L) (data not shown). The distribution of febrile episodes according to treatment phase of leukemia and the total number of neutropenic and lymphopenic febrile episodes are shown in Table 3.

T3-5
TABLE 3:
Incidence of Neutropenic, Nonneutropenic and Lymphopenic Febrile Episodes of 51 Children With Leukemia. Distribution of Hospital Days, Fever Days, Antibiotic Days During Anticancer Treatment

The infections appeared to be community-acquired in 111 cases (78%) and nosocomial in 27 cases (22%). Respiratory viruses tended to be more common among community-acquired febrile episodes compared with nosocomial febrile episodes (P = 0.21). Table 4 shows the clinical signs and symptoms of detected respiratory viral infections. The respiratory viral infections were mild in most cases and progressed to pneumonia in 2 children, 1 with RSV and 1 with rhinovirus (Fig. 2). The mean duration of fever was 2.6 (SD 1.7) days in children with respiratory viral infection and 2.1 (SD 1.3) days in children without viral infection (P = 0.44). Fever lasted for 7 days or more in 6 cases; 4 febrile episodes (including 1 blood culture positive cases) with positive respiratory viral studies and 2 febrile episodes with virus negative studies. All febrile episodes except 3 were treated with broad-spectrum antibiotics, usually with cloxacillin and ceftazidime. Antibiotic therapy was usually continued even if some viral tests turned to be positive. Specific antiviral treatment was given to 1 child with influenza A infection (zanamivir) and 1 child with varicella zoster infection (acyclovir). Two children died; one of Streptococcus mitis septicemia with rhinovirus in nasal swab samples and another of invasive aspergillosis with rhinovirus in the nasal swab samples identified 4 times during the 2 weeks preceding death.

T4-5
TABLE 4:
Signs and Symptoms of Febrile Respiratory Virus Infections in Children With Leukemia

The first mean serum CRP concentration in the febrile episodes caused by sole respiratory viral infection (n = 37) was 32 mg/L (SD 27; range, 1–195; normal values, <10 mg/L) compared with 67 mg/L (SD 46; range, 5–306) in febrile episodes with blood culture positive septicemia (n = 19) (P = 0.04). The mean CRP value of the febrile episodes whose microbiologic studies remained negative (n = 17) was 30 mg/L (SD 28; range, 1–160).

DISCUSSION

We found evidence of respiratory viral infection in 44% of the febrile episodes in children with leukemia. Rhinovirus and RSV were the most frequently detected viruses. Recently discovered HBoV was found in 3 children, 1 with 5 consecutive episodes. The strength of our study is that it was a prospective survey in 4 centers and encompassed for 5 years. The survey covered many respiratory virus outbreaks, and 12 types of respiratory virus were searched for using several virologic techniques.

There are only a few studies of respiratory viral infections in children with cancer (Table 5). This may be the result of limited virologic expertise and effective therapy. The occurrence of respiratory viral infections has varied between 8% and 43%.2,3,12,24–28 Arola et al3 studied 75 febrile episodes in 32 children with malignancy and found evidence of respiratory viral infection in 37% of the cases, using virus culture, antigen detection, and serology for the detection of viral infection. Möttönen et al2 studied the incidence of viral infections in 15 children with ALL and compared their findings with those in 26 healthy controls. They reported that children with ALL had more infections than healthy controls, and respiratory infections were the most common infections in both groups. Viral causation was found twice as often in children with ALL as in their controls (47 versus 22 cases). Rhinovirus, RSV, parainfluenza viruses, enteroviruses, adenovirus, and influenza viruses were the most common viruses detected in these 2 studies.2,3 Only 1 previous study has used PCR techniques to detect respiratory viruses. A 12-month follow-up study in Denmark used oral washes to investigate viruses as a cause of 250 febrile episodes in 66 children with ALL.12 A diluted oral wash may not be the optimal sample, and respiratory viruses were found only in 11% of febrile episodes. In agreement with our findings, many studies have shown that PCR techniques are more sensitive than virus culture, especially for rhinovirus and enteroviruses,5,6,19 and more studies on respiratory viruses with PCR in immunocompromised children are needed. It should be noted that the causative viral agent of respiratory infections in children can now be determined in up to 95% of the cases with clinically suspected viral infection.20

T5-5
TABLE 5:
Prospective Studies on Respiratory Viral Infections in Children With Cancer

Rhinovirus is the most common virus detected from patients with respiratory infection, and it was commonly detected in children with leukemia as well. Most of the infections were mild, in agreement with the study of Arola et al3 of 13 immunosuppressed children. The fall and spring prominence of rhinovirus reflects seasonal occurrence. In a study of Bowden et al29 of adult bone marrow transplant recipients, rhinovirus accounted for 25% of the respiratory infections and was the third most common viral agent after RSV and parainfluenza viruses. Ghosh et al30 studied the clinical course and outcome of rhinovirus infection in 22 adult myelosuppressed patients. The majority of the illnesses did not progress beyond upper respiratory tract infection, but severe pneumonia with a fatal outcome was reported in up to 32% of the cases, which is in agreement with reports on other respiratory viral infections in adults with hematologic malignancies.31 Both Bowden29 and Gosh30 used PCR to detect rhinovirus. Recently, Kaiser et al32 reported chronic rhinovirus infections from a 12-month period associated with graft dysfunction in 3 of 68 adult lung transplant recipients. In our study, rhinovirus was positive in 31 febrile episodes of 18 children with leukemia, and in 2 cases it was associated with a fatal outcome, one because of bacterial septicemia and the other because of fungal infection.

Data on the antiviral treatment of respiratory viral infections in immunocompromised children are limited. In adults, the efficacy of oseltamivir has been studied to limit the extent of infection associated with influenza, and the benefits of aerosolized ribavirin, to limit the extent of infection associated with RSV.33 On a compassionate basis, pleconaril can be used for picornavirus infections.34

Earlier, the causative agent of a large proportion of febrile episodes of immunocompromised hosts has gone undetermined. Lex et al35 studied infectious complications in 112 children with ALL or T-cell lymphoma. Fever was recorded in 24% of the chemotherapy cycles, and 40% of these cases were considered as febrile episodes of unknown origin. Lehrnbecher et al36 prospectively analyzed 855 febrile episodes in 344 children with AML, and in 61% of these episodes no source or etiology could be determined. Furthermore, Katsimpardi et al37 analyzed 610 infections in 86 children with ALL during the entire treatment of leukemia. They found upper respiratory tract infection in 40% of the febrile episodes during the maintenance treatment of leukemia, but a specific viral diagnosis was made in only 10% of the infections. In our study, respiratory viruses were detected in 44% of the febrile episodes. This suggests that many cases of febrile episodes with unknown origin in the past may have been caused by respiratory viral infections.

Recently, lymphopenia has been recognized as a risk factor for severe respiratory syncytial virus infection in children with cancer or other underlying disease.38 The role of lymphopenia for patients recovering from hematopoietic stem cell transplantations has been studied mostly among adult patients. Nichols et al33 reported that lymphopenia was associated with increased susceptibility to develop severe influenza A disease after transplantation. Interestingly, in our study, lymphopenia tended to be more common among children with respiratory viral infections than in other febrile children with leukemia. Whether lymphopenia is a real risk factor for respiratory viral disease or, moreover, a consequence of the viral disease, remains unsolved in this study.

The limitations of our study should be emphasized. We searched for many viruses, but not in all episodes included in the study. In addition, we could probably have increased our yield of respiratory viruses if more viruses like coronavirus HKU1, coronavirus NL63, parainfluenza virus type 4, and influenza C virus could have been searched for.20 Furthermore, all respiratory viruses were not searched for by PCR, which is more sensitive than antigen detection for detecting respiratory viruses, especially parainfluenza viruses and adenovirus.39–44 It is likely that the role of respiratory viruses in our febrile children with cancer were underestimated. The clinical importance of a positive rhinovirus PCR test can be questioned because several studies have identified rhinovirus RNA in 12–35% of asymptomatic subjects.45 Also positive HBoV PCR test needs to be considered with caution because of the high rate (33–56%) of other respiratory viruses in these children.46–50 On the other hand, it has recently been shown that most HBoV-positive children develop a specific IgM and/or IgG response.51 In our study, most follow-up samples studied were negative, but the persistence of viruses needs to be studied more thoroughly. As earlier studies have shown, immunosuppressed patients may have prolonged viral shedding of rhinovirus, RSV, influenza, and parainfluenza viruses compared with immunocompetent hosts, and on the other hand, some viruses like HHV-6 or parvoviruses may reactivate during immunosuppression.52

In conclusion, our findings suggest that respiratory viruses are common in febrile children with leukemia. In 13% of the cases, respiratory viruses were associated with bacterial septicemia. Most of the viral infections were mild upper respiratory tract infections, which rarely progressed to pneumonia. However, all febrile infections of children undergoing treatment for cancer are managed with broad-spectrum antibiotics, often necessitating hospitalization. Controlled surveys are needed to study whether mild febrile respiratory infections in children with cancer could be managed without antibiotics.

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Keywords:

respiratory; virus; rhinovirus; leukemia; cancer; children; fever

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