Influenza A (H1N1) pneumonia: a brief review La polmonite da influenza A (H1N1): una breve review

Review article / Articolo di revisione

Rassegna di Patologia dell’Apparato Respiratorio 2012; 27: 333-337 333

Antonello Nicolini (foto)

Catia Cilloniz*

Division of Respiratory Diseases, General Hospital of Sestri Levante, Sestri Levante, Italy; * Department of Pneumology, Institut Clinic del Tórax, Hospital Clinic of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Ciber de Enfermedades Respiratorias (Ciberes) Barcelona, Spain

Key wordsInfluenza A H1N1 virus • Pandemic  • Pneumonia

Parole chiaveInfluenza A H1N1 • Pandemia • Polmonite

Ricevuto l’8-5-2012.

Accettato il 13-9-2012.

*Antonello NicoliniUO Pneumologiavia Terzi, 4316039 Sestri Levante (Ge)antonello.nicolini@fastwebnet.it

SummaryPandemic influenza A (H1N1) virus emerged in Mexico during the spring of 2009 and spread rapidly and caused significant strain on health systems worldwide. The clinical picture of the pandemic influenza A (H1N1) virus ranges from a self-limiting a-febrile infection to a rapidly progressive pneumonia. The presence of less co-morbidity, more extensive respiratory compromise, and ICU admission are key features of the clinical pre-sentation of patients with novel H1N1-associated pneumonia compared with other viruses and in particular seasonal influenza pneumonia. Bacterial co-infections, particularly Streptococcus pneumoniae, increased the severity of illness and consumption of health resources. Patients from the post-pandemic period had an unex-pectedly high mortality rate and showed a trend towards affecting a more vulnerable population, much like more typical seasonal viral infection. Early use of non-invasive ventilation in severe cases of acute respiratory failure required shorter ventilation time as well as shorter ICU stay and hospital stay.

RiassuntoLa pandemia di influenza A (H1N1), virus apparso in Messico durante la primavera del 2009 e diffusosi rapi-damente in tutto il mondo, ha causato un significativo impegno di tutti i sistemi sanitari. Il quadro clinico della pandemia influenzale A (H1N1) varia da un infezione autolimitante a-febbrile ad una polmonite rapidamente progressiva. Le presenza di minori comorbilità, una compromissione respiratoria più ampia, un più frequente ricorso al ricovero in terapia intensiva sono le caratteristiche osservate maggiormente nei soggetti affetti da polmonite causata da virus influenzale H1N1 rispetto a quanto finora osservato in polmoniti causate da altri tipi di virus, in particolare da quello dell’ influenzale stagionale. La presenza di co-infezioni batteriche (in par-ticolare da Streptococcus pneumoniae) aumenta la severità del quadro clinico e di conseguenza il consumo di risorse. Nel periodo post-pandemico (seconda ondata) l’infezione ha provocato un tasso di mortalità più elevata del previsto, ha mostrato una tendenza a colpire una popolazione più vulnerabile, in linea con una modalità più tipica dell’influenza stagionale. L’utilizzo precoce della ventilazione non invasiva nei casi di insuf-ficienza respiratoria acuta severa ha reso il tempo di ventilazione più breve, più breve la degenza in terapia intensiva, come pure la durata del ricovero ospedaliero.

EpidemiologyFrom the beginning of the epidemic,

Influenza A H1N1 infection seemed to have a more severe course and worse outcomes than did infection with seasonal influenza A. In addition, the demographic profile of influenza A H1N1 infection was younger; moreover, it affected individuals with fewer co-morbidities 1.The incubation period of H1N1 is similar to that of sea-sonal flu with some striking differences. A quarter of all patients with pandemic flu presented with gastrointestinal symp-toms and approximately 40% of all hos-pitalized patients had findings consistent with pneumonia on initial chest X-rays. In

addition 10-30% of hospitalized patients required admission to ICUs and mechani-cal ventilation 1.

The most notable difference in routine laboratory tests is in the white blood cell (WBC) count. In human seasonal influenza A, leucopenia is common and a predictor of severity. However, in H1N1, leukocyto-sis is the rule and is associated with fever, dry cough, severe myalgias, otherwise unexplained thrombocytopenia, relative lymphopenia plus mildly elevated serum transaminases and elevated creatine phos-phokinase 2.

Female and individuals between 20 and 39 years of age present the highest risk of mortality (median age of 26 years).

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Complications leading to hospitalization and pos-sibly death can occur in some of subjects, especially those affected by underlying medical conditions in-cluding diabetes mellitus, pulmonary, cardiovascular, neurologic and psychiatric diseases.

A quarter of all patients with pande-mic flu presented with gastrointestinal symptoms and approximately 40% of all hospitalized patients had findings consistent with pneumonia.

Obesity (BMI ≥ 30) and morbid obesity (BMI ≥ 40) was an independent risk factor for morbidity and mortality from pandemic influenza A H1N1  3: a high number of obese subjects were among the more se-vere cases 4.

Complications leading to hospita-lization and possibly death can occur in some of subjects, especially those affected by underlying medical condi-tions.

This particular susceptibility to respiratory infection may be the result of a concurrence of mechanical and hormonal factors due to the excess weight. Another important risk factor for severe disease was preg-nancy 5. During 2009 H1N1 pandemic hospitalization rate was significantly higher among pregnant than non pregnant 6. Maternal obesity and smoking during preg-nancy were also associated with hospital admission and more severe disease. Women admitted to hospital with influenza A H1N1 infection were more likely to de-liver preterm 6.

Obesity (BMI ≥ 30) and morbid obe-sity (BMI ≥ 40) was an independent risk factor for morbidity and mortality from pandemic influenza A H1N1.

A lower respiratory tract involvement was seen from 19% to 50 % of the diagnosed H1N1 virus infection patients  7. The impact of co-infection was reported in several studies, particularly bacterial co-infections. Mixed respiratory viral co-infections were often less studied  8. The most common viruses detected were rhinovirus, enterovirus, bocavirus, coronavirus OC43 and parainfluenza virus 3. Patients with viral co-infec-tion showed a trend towards higher rates of pneumo-nia and hospital admission. In addition, the duration of hospitalization was significantly longer than in those without co-infection, possibly reflecting a more se-vere clinical course 8. Bacterial co-infection has been reported with rates between 0%  7 and 28%  9.The commonest bacterial culprit was Streptococcus pneu-moniae 8, followed by Mycoplasma pneumoniae, Sta-phylococcus aureus, Klebsiella pneumoniae, Moraxella

catarrhalis, Pseudomonas aeruginosa, Streptococcus pyogenes and Streptococcus agalactiae 8 10. Bacterial co-infection was more frequent in patients aged more than 50 years of age. The presence of underlying co-morbidity increased the risk for bacterial co-infection.

ICU admissions, mechanical ventilation, renal im-pairment and mortality were notably higher in patients with bacterial co-infections. Moreover, leukocyto-sis and neutrophilia were more common in bacterial co-infected patients. Relative lymphopenia has been considered a non-specific laboratory test indicator of influenza A H1N1 pneumonia 2. Leukocytosis and neutrophilia have been regarded markers of bacte-rial co-infection. Lymphopenia lower than 800/ml was associated with a worst outcome 11. Invasive aspergil-losis after infection with influenza A H1N1 virus have been recently described in five patients: all the pa-tients were admitted to intensive care unit and two of them died 12.

Clinical and radiological findings

Pneumonia is the most common complication of influenza A H1N1. Primary viral pneumonia is defined in patients who presents during the acute phase of influenza virus illness with respiratory symptoms and unequivocal alveolar opacification with negative res-piratory and blood bacterial cultures  13. Although rapid antigen tests had a lower sensitivity (10% to 51%) and could not differentiate novel H1N1 from other strains of influenza A they were used early in the pandemic. Consequently, negative rapid tests can-not exclude the diagnosis 22. At present,the preferred test is RT-PCR. It has a sensitivity of 98%, a positive predictive value of 100%, and a negative predictive value of 98% 11 13. Among hospitalized patients with H1N1 pneumonia, about 26% had an infiltrate limited to one lobe on chest X ray and 22.9%-49% of this co-hort presented rapidly progressive acute respiratory failure  13  14. Influenza A H1N1 pneumonia occurs in about 20-70% of admitted patients. In severe cases of H1N1 infection, dyspnea usually progresses rapidly within 24 - 48 h with severe respiratory failure asso-ciated with bilateral infiltrates on chest radiographs. Patients with mixed co-infections pneumonia are usu-ally older, have higher level of procalcitonin and higher scores of severity.

Various degrees of bilateral multifocal lesions of ground-glass opacities associated or not with con-solidations (Figure  1); these lesions are both bron-chocentric and centrilobular and often multifocal  15. Bilateral, symmetric and multifocal areas of consoli-dation, often associated with ground-glass opaci-ties are the predominant findings in pediatric patients and are often associated with a more severe clinical course 16. Other rarer radiological manifestations were atelectasis, pneumothorax, pneumomediastinum, and subcutaneous emphysema, ascribed to ARDS  16 17.

H1N1 pneumonia

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Small pleural effusions are common; additional findings include cavitation, necrosis and bronchial thickening 17. Aviram et al. reviewed 97 admission chest radiographs of influenza A H1N1 patients to determinate predict-ing factors of clinical outcome: bilateral opacities and involvement of multiple lung zones were common and occurred significantly more frequently in patients with more severe morbidity (invasive mechanical ventilation) and death 17 18 (Figure 2).

Among patients admitted to an ICU between 32.7% and 62.5% had hypotension requiring vasopressors 19

and between 13% and 59% developed acute renal failure  20. Patients who had refractory hypoxia and hypotension not improving despite good therapeutic strategies usually died from secondary multi-organ fail-ure. Overall mortality reported was between 2.7% and 11.0% and was highest (18%-20%) in patients young-er than 65 years  13 21. Mortality among patients who required mechanical ventilation was quite high (from 21.3% and 45.5%)  13.Only twelve studies from eight countries in Europe, the Americas, the western Pacific

and Asia were published concerning number of deaths or mortality rate due to 2009 pandemic: data are not available for Africa and southeast Asian countries. Be-cause of the absence of global data, the number of deaths and the mortality rate in the world has been likely underestimated 21.

Post-pandemic infection targeted patients with a worse basal condition than those of the 2009 pandemic: they were older, had more chronic comorbi-dities and more advanced clinical pre-sentation on admission.

Post-pandemic infection period targeted patients with a worse basal condition than those of the 2009 pandemic infection. Patients from the post-pandemic (second wave) were older, had more chronic comor-bidities, had more advanced clinical presentation on admission, higher severity scores, increased com-munity-acquired respiratory co-infection (particularly Streptococcus pneumoniae), septic shock, and an increased requirement for mechanical ventilation than those from the pandemic period. In addition patients from the post-pandemic received empiric antiviral treatment less frequently and later in their hospitaliza-tion, and had a higher mortality rate. The second wave attacked a more vulnerable population (COPD, diabe-tes, HIV patients), similarly to the pattern of typical sea-sonal viral infection 22.

Studies of patients admitted to ICU found three fac-tors independently associated with in hospital death: requirement of invasive ventilation, any co-existing morbidity, and older age 13. Some laboratory findings such as transaminases, LDH were positively correlated with the number of pulmonary lobes involved and the severity of the outcome 23.The patients at highest risk of developing complications include children younger than five years or persons 65 years or older, pregnant women and those with chronic underlying medical conditions (particularly asthma, but including other pulmonary, cardiac, hematologic, hepatic, neurologic, and metabolic diseases). Also at higher risk are immu-nocompromised patients, residents of long-term care facilities and obese patients 24. A longer interval from onset of symptoms to treatment, concurrent underly-ing conditions such as pregnancy were related to the severity of illness too 25.

A recent study evaluated the role of community-acquired severity scores as predictors of severity and mortality for patients affected by Influenza A H1N1 pneumonia 26: the conclusions were that current com-munity-acquired (CAP) severity scores (PSI, CRB-65, CURB-65) fail to predict actual mortality in a significant number of hospitalized patients and underestimate the severity of illness. Moreover, the authors found that obesity and wheezing were the only novel vari-ables associated with mortality. Traditional markers of pneumonia severity as CAP scores, serum lactate and

Figure 1. Chest computed tomography in patient presen-ting bilateral lobar densities.

Figure 2. Chest computed tomography in a patient with bilateral and multifocal areas of consolidation associated with ground-glass opacities (often associated with a more severe clinical course).

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ported high rates of NIV failure in pandemic influenza A H1N1 pneumonia and early non-invasive ventilation was strongly not recommended 33. However, other authors have more recently reported some cases demonstrating the effectiveness of NIV in severe respiratory failure re-lated to H1N1 pneumonia 34 35. Early use of non-invasive ventilation severe cases of acute respiratory failure have achieved a success rate of up 40%.Patients success-fully treated required shorter ventilation time, shorter ICU and hospital stay. Their mortality rate has been similar to those intubated at admission 36.

ConclusionsInfluenza A H1N1 virus produces a higher incidence

of severe outcomes in younger people: most of them present with pneumonia. Obesity, pregnancy and sever-al pre-existing conditions such as respiratory, cardiovas-cular, and immune-hematological disorders, higher lev-els of C-protein reaction and delay in medical care were predictive factors for pneumonia in adult patients  37. Younger age, less co-morbidity, more extensive respira-tory compromise, and ICU admission are key features of the clinical presentation of patients with novel H1N1-as-sociated pneumonia compared with other viruses and in particular seasonal influenza pneumonia  1. Bacterial co-infections, particularly Streptococcus pneumoniae, increased the severity of illness and consumption of health resources  37 38. Patients affected by influenza A H1N1 during post pandemic (second wave) period were older, had more chronic co-morbid conditions, had greater severity of illness and received empiric antiviral treatment less frequently and later than first wave pa-tients. They had an unexpectedly higher mortality rate, representing a more vulnerable population 22.

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Therapeutic strategiesAt the present, with few exceptions, influenza A

H1N1 virus remains susceptible to the neuraminidase inhibitors oseltamivir and zanamivir, but resistant to the M2 inhibitors amantadine and rimantadine  13. In mild cases oseltamivir when given early (≤ 2 days after on-set of symptoms) can shorten the duration of symp-toms; for high-risk patients or patients with severe or progressive clinical illness, oseltamivir or zanamivir should be initiated immediately or as soon as possi-ble (ideally within 48 hours of the onset of illness) 13 28. A total of 264 oseltamivir-resistant pandemic influ-enza A H1N1 viruses have been identified since the end of 2010. These resistant organisms demonstrate a H275Y mutation which causes resistance to osel-tamivir, but not to zanamivir  13. The risk of resistance is considered higher in patients who have prolonged illness or have received antiviral treatment for an ex-tended duration 13. Some adult cases of oseltamivir-re-sistence have been reported in Korea and in Spain with a single exception; they have not been fatal 29. Nausea and vomiting are the most common adverse effects to these anti-viral agents. Less common are neuropsychi-atric reactions 30. Antimicrobial treatment should follow the recommendations of IDSA/ATS guidelines: use a beta-lactam agents in combination with a macrolide or a respiratory fluoroquinolone. The use of antibiotics against MRSA (such as vancomycin or linezolid) should be limited to patients with confirmed MRSA infection or with a compatible clinical presentation (shock and necrotizing pneumonia) and in patients admitted to ICU 9. Treatment of corticosteroids in patients with se-vere H1N1 infection is still controversial and has dem-onstrated no improvement in survival 22 30.

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