Increased Incidence of Eosinophilia in Severe H1N1 Pneumonia during 2015 Influenza Season

Benjamin Deaton MD

Nicholas Villalobos MD

Andrea Mytinger DO

Michel Boivin MD

Department of Internal Medicine

University of New Mexico School of Medicine

Albuquerque, NM USA

Abstract

Background: A portion of patients with influenza develop a severe, life t-threatening illness requiring intensive care. We observed a significant number of critically ill influenza patients with eosinophilia during the 2015 influenza season in New Mexico.

Methods: Patients were identified sequentially by reviewing disposition records of all patients admitted to the University of New Mexico Hospital medical intensive care unit between October 2015 and May 2016 for a diagnosis of influenza.

Results: Eleven patients were identified who developed respiratory failure from influenza. Average age was 43.7 + 11.3 (SD) with an average SAPS-2 score of 52.0 + 13.9 (SD) on admission. All 11 were found to have H1N1 influenza. All 11 required mechanical ventilation vasopressor support. Ten patients survived. Notably, 6 (54.5%) developed peripheral eosinophilia (>300/μL) during their hospitalization and all but one of these did not have peripheral eosinophilia at the time of admission. Bronchoalveolar lavage was performed in 5 patients (45.5%) and none were consistent with eosinophilic pneumonia. Further data analysis revealed exploration revealed no significant differences in multiple parameters and no clear cut cause of drug-induced eosinophilia was identified.

Conclusion: During the 2015 influenza season in New Mexico, a disproportionate number of patients with H1N1 influenza and respiratory failure developed peripheral eosinophilia. Type 2 errors could have occurred due to low sample size. Given the unusual frequency of peripheral eosinophilia further studies regarding the association of influenza A and peripheral eosinophilia is warranted.

Introduction

Influenza pneumonia remains a cause of significant morbidity and mortality (1). The re-emergence of H1N1 influenza in 2009 was associated with particularly severe respiratory illness, acute respiratory distress syndrome (ARDS) and mortality (2). The ARDS associated with H1N1 influenza appeared to disproportionately affect younger individuals, compared to other strains of influenza A (2). During the 2015 influenza season H1N1 circulated relatively late in the southwestern United States (3). Intensivists caring for patients with severe H1N1 pneumonia at the University of New Mexico hospital noticed a series of cases associated with significant peripheral eosinophilia. Eosinophilia with influenza or its treatments has rarely been described (4). We therefore sought to examine all cases of severe influenza pneumonia during the 2015 influenza season for the prevalence of peripheral eosinophilia and to assess for potential associations.

Methods

This study was reviewed and approved by the Institutional Review Board of the University of New Mexico Health Sciences Center. Patients from the University of New Mexico Hospital (UNMH) adult Medical Intensive Care Unit (MICU) admitted between October 2015 through May 2016 were retrospectively screened for inclusion. Inclusion criteria included a diagnosis of influenza (using a PCR based assay of nasal swab), admission to the UNMH MICU and age ≥ 18 years. Exclusion criteria included patients admitted to the MICU where influenza did not lead to significant respiratory failure.

In this retrospective cohort chart review, data was collected for demographics, clinical parameters at presentation and throughout their hospital course, and interventions received. Patients were assessed for the presence of eosinophilia at any point during their hospital course. Eosinophilia was defined as a serum eosinophil count that exceeded the upper limit of normal on a complete blood count (0.3x10³ cells/microliter). Values are reported with their standard deviation. Statistical analysis was performed using Stata 14 for Mac. The data was explored using two-sided t-tests, Fisher’s exact and Chi-squared tests between the 2 groups with and without eosinophilia. The paper was partially presented in poster form at the 2017 American Thoracic Society International Congress in Washington, DC (5).

Results

Thirteen patients with influenza were identified. Two patients were excluded from further analysis as they did not meet the criteria of having respiratory failure, the remaining eleven were included in this study. The average age of patients in the study was 43.7 ±11.3 years with an average SAPS-2 score of 52.0 ± 13.9 on admission. All eleven patients in the study admitted with severe influenza A leading to respiratory failure during the 2015-2016 influenza season were found to be infected by the H1N1 strain of influenza. See Table 1 for further descriptors of the cohort.

Table 1. Baseline and treatment characteristics by group.

The peak eosinophil count of the group with normal eosinophil count was 0.1(+0.1) X10³ cells/µl compared to 1.9 (+ 2.1) X10³ cells/µl in the group with significant peripheral eosinophilia (p=0.06). The range of eosinophilia in the group with normal eosinophil count was 0.0-0.3 X10³ cells/µl, and 0.5-4.8 X10³ cells/µl in the group with eosinophilia. The group with normal eosinophil count reached a “peak” count after an average of 4.6 days, and the group with an elevated eosinophil count after 17.1 days (p<0.02).None of the patients who underwent bronchoscopy had a significant elevation in the bronchoalveolar lavage eosinophil count.

Discussion

During the 2015-2016 influenza season in New Mexico, critically ill patients at UNM hospital admitted with influenza pneumonia were infected with the H1N1 subtype. Over 50 percent of these patients developed peripheral eosinophilia at some point of their hospital course. Among those who underwent bronchoscopy, significant alveolar eosinophilia was not observed, suggesting against a pulmonary cause of eosinophilia, such as acute or chronic eosinophilic pneumonia. All patients were treated with oseltamivir, so an association with this treatment could not be determined. No demographic differences were noted between patients who vashad peripheral eosinophilia and those that did not. The patients with significant peripheral eosinophilia trended to have a longer ICU and hospital length of stay (LOS) but this did not reach statistical significance in this small cohort.

Type 2 errors (failure to detect a true difference between groups due to small numbers of subjects) could have occurred due to low sample size while exploring etiologies. Potential etiologies that could have explained the observed eosinophilia included drug effect, possibly due to oseltamivir, antibiotics, diuretics or other medications. A review of the literature reveals case reports of associations between eosinophilia and influenza vaccine (6,7). Acute eosinophilic pneumonia has also been associated with H1N1 infection, but eosinophilia was not demonstrated on broncho-alveolar lavage in our series (8.9). Potentially this could have been a reaction to epitopes of this particular strain of H1N1 influenza. However, there have yet to be reports of eosinophilia during the 2015-2016 influenza season in the literature. Perhaps local factors could have contributed to an increased incidence of significant peripheral eosinophilia. Anecdotally, the authors do not however recall an increased incidence of eosinophilia in patients admitted for diagnoses other than H1N1. Patients were screened for other causes of viral pneumonia, and there was no clear co-infection that was associated with influenza associated eosinophilia. It was also noted the time to peak eosinophil count was much later in the elevated eosinophil group, and in most it took 14 days for the count to peak. This suggests the stimulus for the eosinophilia was ongoing for considerable time during the admission.

In conclusion, we describe an unusually high incidence of peripheral eosinophilia in patients with severe H1N1 influenza during the 2015 flu season. This eosinophilia was not associated with alveolar eosinophilia. Further observation for the recurrence of this association of H1N1 influenza A and peripheral eosinophilia is warranted during future influenza seasons.

References

1. Rotrosen ET, Neuzil KM, Influenza: a global perspective. Pediatr Clin North Am. 2017;64:911-36. [CrossRef] [PubMed]
2. Davlin SL, Blanton L, Kniss K, et al. Influenza Activity - United States, 2015-16 Season and Composition of the 2016-17 Influenza Vaccine.MMWR Morb Mortal Wkly Rep. 2016 Jun 10;65(22):567-75. [CrossRef] [PubMed]
3. Uyeki TM. Influenza. Ann Intern Med. 2017 Sep 5;167(5):ITC33-ITC48. [CrossRef] [PubMed]
4. Deaton, BR., Mytinger, AK, Ahmed, S, et al. Peripheral eosinophilia associated with 2016 H1N1 influenza. Am J Resp Crit Care. 2017;195:A5787 [Abstract],
5. Hayashi R, Shimomura N, Hosojima M, et al. A case of non-episodic angioedema with eosinophilia induced by influenza vaccine. Eur J Dermatol. 2017;27:554-5. [CrossRef] [PubMed]
6. Solak B, Dikicier BS, Kara RO, Erdem T. DRESS syndrome potentially induced by allopurinol and triggered by influenza vaccine. BMJ Case Rep. 2016 Mar 30;2016. [CrossRef] [PubMed]
7. Larrañaga JM, Marcos PJ, Pombo F, Otero-González I. Acute eosinophilic pneumonia as a complication of influenza A (H1N1) pulmonary infection. Sarcoidosis Vasc Diffuse Lung Dis. 2016 Mar 29;33(1):95-7. [PubMed]
8. Jeon EJ, Kim KH, Min KH. Acute eosinophilic pneumonia associated with 2009 influenza A (H1N1). Thorax. 2010;65:268-70. [CrossRef] [PubMed]

Cite as: Deaton B, Villalobos N, Mytinger A, Boivin M. Increased incidence of eosinophilia in severe H1N1 pneumonia during 2015 influenza season. Southwest J Pulm Crit Care. 2018;16(3):146-9. doi: https://doi.org/10.13175/swjpcc021-18 PDF 

Corticosteroids and Influenza A associated Acute Respiratory Distress Syndrome

Philippe R. Bauer, MD, PhD

Vivek N. Iyer, MD, MPH

Pulmonary and Critical Care Medicine

Mayo Clinic

Rochester, MN USA

Abstract

The use of corticosteroids remains controversial in influenza infection, especially with lower respiratory tract infection. We present a case of moderate acute respiratory distress syndrome (ARDS) associated with influenza A that showed a dramatic improvement with combined corticosteroids and antiviral therapy. Host defense against virus infection consists of both innate and adaptive immune responses. An exuberant immune response to the primary pathogen leads to ‘collateral’ lung damage resulting in ARDS.  The use of corticosteroids to modulate this excessive immune response, although intuitive, has been associated with increased mortality when administered early in the course of severe influenza A pneumonia. The administration of corticosteroids in this case was associated with a dramatic and unequivocal improvement. This unique case highlights the potential benefits of corticosteroids use in influenza A associated ARDS and may challenge clinicians to rethink current recommendations that specifically discourage corticosteroids use in patients with Influenza A associated ARDS.   

Introduction

The impact of corticosteroids on clinical outcome in patients with influenza A associated respiratory failure is unclear (1). Retrospective studies suggest an adverse effect from early parenteral corticosteroids use in patients with pandemic influenza infection. On the other hand, in immunosuppressed patients, high dose corticosteroid given at the time of diagnosis of influenza was associated with a reduced risk for mechanical ventilation, without increased adverse effects other than delayed viral clearance. In general, the effect of corticosteroids on acute respiratory distress syndrome (ARDS) is controversial and its use is not routinely recommended. The adjunctive use of prednisone during the early phase of community-acquired pneumonia may actually reduce the development of ARDS (2). In severe influenza, early corticosteroids showed no evidence of benefit and suggested potential harm (3). We present a case of moderate ARDS associated with influenza A that showed a dramatic and unequivocal improvement after initiation of corticosteroids.

Abbreviations:

APACHE: Acute Physiology and Chronic Health Evaluation

ARDS: Acute Respiratory Distress Syndrome

ICU: Intensive Care Unit

PCR: Polymerase Chain Reaction

SOFA: Sequential Organ Failure Assessment

Case Report

A 62-year old male, nonsmoker, with a history of hypertension, dyslipidemia and depression, presented in March 2014 with chills, fever and nonproductive cough; he was initially treated for ‘bronchitis’ as an outpatient with levofloxacin. He had not received the influenza vaccine. Three days later, he developed acute hypoxemic respiratory failure with bilateral pulmonary infiltrates and was hospitalized elsewhere. Influenza testing was negative and he was started on piperacillin/tazobactam and azithromycin. He was transferred to our facility the next day because of worsening respiratory status. Initial heart rate was 80 bpm, blood pressure was 120/60 mm Hg, respirations was 22/min, and temperature was 37.7 ºC. The Acute Physiology and Chronic Health Evaluation (APACHE) IV score was 55 and the Sequential Organ Failure Assessment (SOFA) score was 8. His presentation was consistent with moderate ARDS with a PaO₂/FiO₂ ratio of 143, a chest radiograph showing bilateral pulmonary infiltrates (Figure 1) and no evidence of heart failure confirmed by bedside echocardiogram.

Figure 1. Bilateral pulmonary opacities consistent with moderate ARDS (PaO₂/FiO₂ ratio 143).

Nasal swab was again negative for influenza by polymerase chain reaction (PCR). Leukocyte count was 4.4 x 10⁹/L with lymphopenia (0.22 x 10⁹/L), hemoglobin was 11.7 g/dL, and platelet count was 216 x 10⁹/L. Sodium was 134 mmol/L, creatinine was 1 mg/dL and AST was 142 U/L. He was initiated of high flow nasal oxygen, and vancomycin and oseltamivir were added. Due to the severity of his condition, he was also started on methylprednisolone (125 mg intravenously every 8 hours). After a brief trial of noninvasive ventilation, he was intubated, sedated, paralyzed and placed on a low tidal volume strategy with an initial PEEP of 15 cm H₂O and a FiO₂ of 0.7. A broncho-alveolar lavage, performed post intubation about 16 hours after admission to our facility, showed 35% alveolar macrophages, 8% lymphocytes and 57% neutrophils and was positive for influenza A by PCR; cultures were negative for other organisms. Other tests including HIV, RSV, Mycoplasma, Legionella and urine for Streptococcus antigen were all negative. The patient improved rapidly. He was extubated two days later, and continued on prednisone (40 mg daily) for five more days when he was dismissed home without any need for supplemental oxygen, although the chest radiograph continued to show infiltrates.

Discussion

This case illustrates a patient with delayed diagnosis and treatment of influenza A associated with moderate ARDS who made a rapid and complete recovery with antiviral, antibiotic and adjunctive high dose corticosteroid therapy. 

The diagnosis of influenza A in this case meets all criteria established by Clinical Practice Guidelines of the Infectious Diseases Society of America (4). Rapid influenza testing lack sensitivity and false negative are not infrequent. ARDS is a well-defined complication of influenza infection. While the administration of corticosteroids appeared to temporally co-relate with clinical improvement, a causal link cannot be established definitively. The role of immunosuppression in influenza associated ARDS is very controversial with conflicting evidence from prospective (supportive) and retrospective (against) studies. For example, the combined use of sirolimus and prednisone was associated with significantly improved oxygenation as well as reduced organ dysfunction in mechanically ventilated patients with severe H1N1 respiratory failure (5). On the other hand, retrospective studies have shown increased mortality with the early use of high dose corticosteroids in severe influenza A pneumonia and respiratory failure. Furthermore, corticosteroids are now rarely used in ARDS and only sparingly given in case of refractory septic shock. The immune response to influenza infection depends on the virus, the host and the host response to infection. Host defense against virus infection consists of both innate and adaptive immune responses. An excessive immune response may result in ‘collateral damage’ and critical respiratory illness which may be ameliorated by the use of systemic corticosteroids. On the other hand, suppression of the host immune system may enhance viral replication and prolong critical illness. As a result of these conflicting data, major societies have been unable to firmly recommend for or against corticosteroids therapy in Influenza A associated respiratory failure.

In conclusion, we report on a case of Influenza A with ARDS and rapid improvement on corticosteroids. We have reviewed the current uncertainty surrounding the use of corticosteroids in this setting and leave open the possibility for careful consideration of this adjunctive therapy in other cases. Randomized trials are needed to further delineate the potential benefit of corticosteroids in severe influenza infection.

References

1. Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J, Lim WS. Corticosteroids as adjunctive therapy in the treatment of influenza. Cochrane Database Syst Rev. 2016 Mar 7;3:CD010406. [CrossRef] [PubMed]
2. Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2015 Apr 18;385(9977):1511-8. [CrossRef] [PubMed]
3. Brun-Buisson C, Richard JC, Mercat A, Thiébaut AC, Brochard L; REVA-SRLF A/H1N1v 2009 Registry Group. Early corticosteroids in severe influenza A/H1N1 pneumonia and acute respiratory distress syndrome. Am J Respir Crit Care Med. 2011 May 1;183(9):1200-6. [CrossRef] [PubMed]
4. Harper SA, Bradley JS, Englund JA, et al. Seasonal influenza in adults and children--diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Insert LinkInfectious Diseases Society of America. Clin Infect Dis. 2009 Apr 15;48(8):1003-32. [CrossRef] [PubMed]
5. Wang CH, Chung FT, Lin SM, Huang SY, Chou CL, Lee KY, Lin TY, Kuo HP. Adjuvant treatment with a mammalian target of rapamycin inhibitor, sirolimus, and steroids improves outcomes in patients with severe H1N1 pneumonia and acute respiratory failure. Crit Care Med. 2014 Feb;42(2):313-21. [CrossRef] [PubMed]

Cite as: Bauer PR, Iyer VN. Corticosteroids and influenza A associated acute respiratory distress syndrome. Southwest J Pulm Crit Care. 2016;13(5):248-51. doi: https://doi.org/10.13175/swjpcc102-16 PDF

December 2015 Critical Care Case of the Month

Samir Sultan, DO 

Banner University Medical Center Phoenix

Phoenix, AZ 

History of Present Illness

The patient is a 32-year-old woman who presented with flank pain for 3 days to an outside hospital. She was diagnosed with pyelonephritis and begun on ceftriaxone. She was discharged against medical advice on cephalexin.

She returned to the same hospital 3 days later by ambulance with labored breathing and weakness and was emergently intubated. She was transferred for ventilator management and respiratory failure.

Past Medical History

She has a long history of poorly controlled diabetes mellitus.

Physical Examination

She is orally intubated and sedated.

Vitals: Temperature - 100.9º F, Blood Pressure - 117/75 mm Hg, Heart Rate - 148 beats per minute,  Respiratory Rate - 31 breaths/min, SpO2 - 88 % on assist control of 30, tidal volume of 350 mL, PEEP 15, and an FiO2 100%.

There is scatted rhonchi and rales but the remainder of the physical examination is unremarkable.

Radiography

Her admission portable chest X-ray is shown in Figure 1.

Figure 1. Admission portable AP of the chest.

Which of the following should be ordered as part of her initial work-up? (Click on the correct answer to proceed to the second of five panels).

1. Administer broad spectrum antibiotics
2. Blood and urine cultures
3. Rapid influenza test
4. 1 and 3
5. All of the above

Cite as: Sultan S. December critical care case of the month. Southwest J Pulm Crit Care. 2015;11(6):246-51. doi: http://dx.doi.org/10.13175/swjpcc147-15 PDF

May 2014 Critical Care Case of the Month: Second Wind

Kenneth K. Sakata, MD

Sudheer Penupolu, MD 

Robert W. Viggiano, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 65 year old woman was admitted for gastrointestinal bleeding as evidence by hematochezia. At the time of admission she denied any respiratory symptoms other than mild dyspnea. However, she rapidly developed respiratory failure, was transferred to the ICU and required emergent intubation.

PMH, FH, SH

She has a history of rheumatoid arthritis with a cervical spine fusion. There is also a history of sarcoidosis and she was receiving prednisone 30 daily up until the time of admission. There is no significant family history. She does not smoke or drink.

Physical Examination

Afebrile. Pulse 78. BP 105/65 mm Hg. Respirations: 28. SpO2 96% while receiving an FiO2 of 60% at the time of transfer to the ICU.

Neck: No jugular venous distention.

Lungs: Scattered rales and rhonchi.

Cardiovascular: Regular rhythm. 

Abdomen: no hepatosplenomegaly.

Radiography

A portable chest x-ray taken after intubation is shown in figure 1.

Figure 1. Portable chest x-ray taken shortly after intubation.

Which of the following best describe the chest x-ray? (Click on the correct answer to move to the next panel)

1. Chronic interstitial disease
2. Diffuse consolidation
3. Endotracheal tube in the right mainstem bronchus
4. Small right pneumothorax
5. All of the above

Reference as: Sakata KK, Penupolu S, Viggiano RW. May 2014 critical care case of the month: second wind. Southwest J Pulm Crit Care. 2014;8(5):258-65. doi: http://dx.doi.org/10.13175/swjpcc033-14 PDF