Pandemic influenza A (2009 H1N1) in children with acute lymphoblastic leukaemia
Dr Susana Rives, Department of Paediatric Haematology, Hospital Sant Joan de Déu de Barcelona, Passeig Sant Joan de Déu nº2, 08150 Esplugues de Llobregat, Barcelona, Spain. E-mail: email@example.com
Pandemic influenza A (2009-H1N1) usually results in mild clinical illness, but in some individuals it can be life-threatening. There are no reports of this disease among paediatric patients with acute lymphoblastic leukaemia (ALL). We report ten consecutive patients with ALL and pandemic influenza treated in a single institution. Median age was 7 years (range: 3–12). All were treated with oseltamivir. There were no deaths. Two patients under intensive chemotherapy developed pneumonia and one required ventilatory support. ALL patients under maintenance treatment had mild disease. In conclusion, in our series only patients under intensive treatment developed a moderate to severe disease.
As of June 2009, swine-origin influenza A (H1N1) was declared a global pandemic. In most cases, pandemic influenza A (2009-H1N1) results in mild clinical illness (Dawood et al, 2009; Hackett et al, 2009). Nevertheless, some individuals infected with this virus can suffer from severe pneumonia, bacterial co-infection and other systemic complications (Centers for Disease Control and Prevention, 2009a,b; Lister et al, 2009; O’Riordan et al, 2009). Risk factors for severe disease are ill-defined, particularly among paediatric cases. Neurological and chronic lung diseases have been identified as major risk factors in paediatric series (Larcombe et al, 2009; Libster et al, 2009; Lister et al, 2009). Immunosuppression is another proposed risk factor (http://www.who.int/csr/resources/publications/swineflu/clinical_management_h1n1.pdf; accessed 20 December 2009), although information regarding evolution of influenza A 2009-H1N1 in immunocompromised patients is very scarce.
Children with acute lymphoblastic leukaemia (ALL) constitute an important group among paediatric immunocompromised patients. Their immunosuppression is both primary to the disease itself and secondary to the chemotherapy they receive, that lasts for 2 years in most patients. Only a minority of them undergo stem cell transplantation, where immunity is further compromised. To our knowledge, there are no specific series reports of pandemic influenza in this population. In order to gather information about pandemic influenza in children with ALL and better understand risk factors for severe disease, we prospectively collected the clinical characteristics of the first ten patients with ALL and pandemic influenza treated in a single institution. This institution is a 345-bed tertiary Maternity and Paediatric Hospital located in Barcelona, Spain. In the Haematology Department 15–20 new paediatric cases of ALL are diagnosed each year. As chemotherapy lasts for 2 years in most patients, 30–40 children with ALL are treated each year in this institution. Informed consent was obtained from all patients and the study was approved by the institutional ethics committee.
Ten ALL patients consecutively diagnosed with pandemic influenza A in a single institution from 25 September to 13 December 2009, during the first pandemic wave (weeks 38–49), were analyzed. During this period, there were 38 patients with ALL that were receiving chemotherapy in our institution; nine were receiving intensive treatment and 29 were on maintenance treatment. Thus, one quarter of our patients with ALL under chemotherapy had laboratory confirmed pandemic 2009-H1N1. In this geographical area, the incidence of pandemic influenza infection among children aged 5–14 years reached its peak between weeks 43 and 46 (1200 infections per 100 000 inhabitants) (Subdirecció General de Vigilància i Resposta a Emergències en Salut Pública, 2010).
Pandemic influenza A was suspected on clinical grounds and diagnosis confirmed by real-time reverse-transcription-polymerase-chain reaction (RT-PCR) for influenza A (2009-H1N1) of nasopharyngeal aspirate. There were eight boys and two girls. Median age was 7 years (range 3–12). Table I summarizes clinical characteristics and outcome of these patients. No patient had received the pandemic influenza vaccination. All of them were in first complete remission and were uniformly treated according to the Spanish Haematology-Oncology Society protocol (ALL-SHOP-2005) (Badell et al, 2008). Eight children were diagnosed while receiving maintenance treatment, with weekly low-dose methotrexate and daily mercaptopurine, and two during intensive chemotherapy. Nine cases were managed on an outpatient basis more than 2 weeks before flu symptoms began. One child was hospitalized for 3 weeks before the onset of influenza.
Table I. Clinical characteristics and outcome of the patients.
|6||Delayed intensification phase||5*||5||Interstitial pneumonia||Non-invasive ventilation (4 d). Inotropic support, NR†||96||Cefotaxime, erythromycin, 3 d Meropenem, teicoplanin, 10 d||Respiratory failure||13||39|
|8||Maintenance||4·9||5||Normal||NR||80||Amoxicillin-clavulanate (10 d)||Fever and leukaemia‡||2||43|
|9||Maintenance||1·3||1||NR||NR||72||Amoxicillin-clavulanate (10 d)||NR||–||44|
|2||Block of consolidation||0·1||3||Interstitial pneumonia||NR||120||Meropenem, teicoplanin 7 d||Chemotherapy§||7§||49|
All patients presented with rhinorrhoea and cough. Nine developed high-grade fever and one had low-grade fever (37·5°C). Three had gastrointestinal symptoms (diarrhoea and vomiting). Median time between the onset of symptoms and medical attention was 2 d. The two patients under intensive chemotherapy had severe neutropenia at presentation or developed it during the 3 d following 2009-H1N1 diagnosis. Patients under maintenance treatment were not neutropenic. No patient had blood analysis that suggested bacterial co-infection at presentation, such as a leucocyte count exceeding 20 × 109/l, C-reactive protein >90 mg/l or procalcitonin >0·7 μg/l. Two patients had an abnormal chest X-ray, with bilateral interstitial pulmonary infiltrates.
H1N1 real-time RT-PCR of nasopharyngeal aspirate was carried out whenever influenza was suspected. Oseltamivir was given empirically not awaiting microbiological confirmation, except for the first patient, in whom treatment was begun 5 d after initiation of fever. All patients received oseltamivir for 5 d except for the two with a greater degree of immunosuppression in whom treatment was kept until achievement of RT-PCR negativity (7 and 15 d).
Six patients were managed on an outpatient basis. Reasons for hospital admission are detailed in Table I. Four children were given antibiotics: following the protocol, for fever and neutropenia in two patients and as a preventive measure in the other two. In eight children blood cultures were performed on the onset of fever; all were negative. There were no deaths and eight had mild disease, with resolution of the fever and good general condition in <72 h after onset of fever.
The first diagnosed patient had a severe pneumonia and required admission on the intensive care unit (ICU). A 6-year-old boy was diagnosed with T-ALL in June 2009 and attained first complete remission after induction chemotherapy. When influenza was diagnosed he was receiving delayed intensification chemotherapy. Intermediate-dose cytarabine was given in the outpatient clinic 7 d before admission for fever and pneumonia. Cefotaxime was started on admission. Oseltamivir was started on the third day of hospitalization, when pandemic influenza was suspected and the RT-PCR in nasopharyngeal aspirate was performed. He was not neutropenic at admission, but became so on the third day of hospitalization, and was due to the cytarabine delivered before admission. Chest X-ray revealed interstitial bilateral infiltrates. On the fourth day of hospitalization, he required admission to the ICU due to severe hypoxaemia and worsening of his interstitial pneumonia. Meropenem, vancomycin and erythromicin were started on ICU admission and oseltamivir continued. He needed non-invasive ventilation support with a bi-level positive airway pressure device for 4 d (maximum parameters were inspiratory positive airway pressure of 15 cm H2O, expiratory positive airway pressure 8, fraction of inspired oxygen 0·4). Blood cultures, PCR for S. pneumoniae in blood, and serological tests for atypical pneumonia bacteria were all negative. He required oxygen (using nasal cannula) for 5 more days and was discharged after 13 d of hospitalization.
Another patient under intensive chemotherapy developed viral pneumonia. A 2 year-old boy admitted to receive a block of consolidation chemotherapy had cough, rinhorrhoea and bronchospasm after 12 d of admission. He developed an interstitial bilateral pneumonia, having severe prostration and high-grade fever for 5 d. He did not develop hypoxaemia but had moderate respiratory distress and required inhalated bronchodilators. Blood cultures, PCR for S. pneumoniae in blood, and serological tests for atypical pneumonia bacteria were negative.
Although seasonal influenza has rarely been associated with severe disease in ALL patients undergoing standard chemotherapy (Whitley & Monto, 2006), there is no information regarding the severity of novel pandemic influenza A in this population. There were no deaths in this series of paediatric ALL patients who suffered from pandemic influenza infection while on chemotherapy treatment. Co-infection was not proven but a simultaneous bacterial pneumonia in addition to the influenza pneumonia cannot be ruled out. Most patients had mild disease and were managed as outpatients without complications. However, one patient had a severe pneumonia requiring ventilatory support.
With regard to the intensity of immunosuppression and outcome, in this series all patients under low-dose chemotherapy had a very mild disease. In contrast, patients that were under high-dose chemotherapy had a more aggressive disease, with severe pneumonia requiring ventilatory support in one and prolonged high fever and pneumonia without oxygen requirement in the other. In this regard, in addition to neutropenia, impaired cell-mediated immunity, also disrupted in ALL patients under intensive chemotherapy (Alanko et al, 1994), could have contributed to the more aggressive course of the influenza in these two patients.
Oseltamivir treatment was given to our patients as a 5-d course following the European Medicines Agency dosages recommendations (http://www.emea.europa.eu/humandocs/Humans/EPAR/tamiflu/tamiflu.htm) except for the two severely immunocompromised patients, in whom we performed serial testing of respiratory specimens and treatment was discontinued only after PCR negativity was achieved. Treatment was prolonged in these patients due to the documentation of prolonged viral shedding in immunocompromised patients, with subsequent emergence of resistance to neuraminidase inhibitor drugs (Centers for Disease Control and Prevention, 2009c). It has been proposed that earlier antiviral therapy may lead to a more profound treatment effect for seasonal influenza (American Academy of Pediatrics [AAP] Committee on Infectious Diseases, 2007). Prompt institution of treatment with oseltamivir was performed in all cases except for the first patient, whose treatment was started on day 5 of symptoms and who had a severe pneumonia requiring ICU admission. However, in addition to treatment delay, greater immunosuppression due to a more intensive chemotherapy treatment could have also contributed to the disease severity in this patient. As all the patients received oseltamivir, the evolution without antiviral treatment cannot be inferred.
No patient had received pandemic influenza vaccination. In most cases, the influenza was diagnosed before these vaccines were available in our country. Although pandemic influenza vaccination efficacy has not been tested in these immunocompromised patients, we are now prescribing it to all our ALL patients, following the Centers for Disease Control recommendations (http://www.cdc.gov/H1N1flu/recommendations.htm; accessed 7 December 2009). Studies with vaccination of seasonal influenza in ALL patients showed that more than 50% of these patients can achieve protective antibody titres (Porter et al, 2004).
More patients are needed to ascertain risk factors for severe disease in paediatric ALL. Nonetheless, we suggest that patients in good clinical condition who are not neutropenic and receive maintenance treatment could be safely managed as outpatients, beginning antiviral treatment as soon as influenza is suspected and not awaiting the result of the RT-PCR. Strict follow-up and guidelines for parents to know when to seek medical attention need to be carefully explained. In our series, children with ALL under maintenance treatment had a mild disease while patients receiving intensive treatment had more severe disease.