Effect Of Exogenous Melatonin on the Incidence of Delirium and Its Association with Severity of Illness in Postoperative Surgical ICU Patients

Dr. Kriti Gupta, MD

Dr. Vipin K. Singh, MD

Dr. Zia Arshad, MD*

Dr. G. P. Singh, MD

*Corresponding Author

Department of Anaesthesiology

King George’s Medical University

Lucknow UP, India 226003

Abstract 

Background: Delirium is common in critically ill intensive care unit (ICU) patients and has been documented in up to 87 percent of patients. Sleep deprivation and delirium have been associated. Alteration of melatonin production has been associated with delirium. Melatonin acts via melatonin receptors present in the suprachiasmatic nuclei (SCN) and promotes sleep by attenuating the wake-promoting signal from the SCN.

Objective: To determine the relationship between exogenous melatonin and the incidence of delirium and its association of with severity of illness, measured in term of APACHE II, procalcitonin level at the time of admission and daily SOFA score.

Patients and Methods:

Design: Randomised placebo-control study.

Setting: the study was conducted in critical care setting in a tertiary level ICU.

Participants: Postoperative patients age between 20-60 years who are going to be ventilated more than 48 hours without any contraindication to enteral medications.

Interventions: Study group received melatonin 5 mg through the enteral route.

Main outcome measures: To determine the effect of exogenous melatonin on the incidence of delirium in postoperative patients who require mechanical ventilation for more than 24 hours. The secondary outcome measures are procalcitonin (PCT) value at admission and disease severity scores like APACHE II and SOFA.

Results: No statistically significant difference was found in admission incidence of delirium or procalcitonin. Age was higher in those patients that developed delirium (p < 0.05).

Conclusions: Although the incidence of delirium is not affected by exogenous melatonin or higher APACHE scores, it had a significant correlation with higher procalcitonin, that in turn indicated an association with delirium and sepsis. It was found that there is increased risk of developing delirium with increasing age.

Key words: delirium, intensive care unit, sedation, melatonin, APACHE II, procalcitonin,

Introduction

Delirium is defined as “A disturbance in attention (i.e., reduced ability to direct, focus, sustain and shift attention) and awareness (reduced orientation to the environment)” (1). Delirium is extremely prevalent in hospitalized patients; it affects 10%–24% of the adult general medicine population and 37–46% of the general surgical population. Delirium has been documented in up to 87 percent of patients in the intensive care unit (ICU) (2). Multiple etiologies have been hypothesized to be causing delirium. Some of these are central cholinergic deficiency, reduced GABA activity, abnormal serotonin and melatonin pathways, cerebral hypo perfusion and neuronal damage due to inflammation (3,4). Acute Physiology and Chronic Health Evaluation II score (APACHE II) and the Sequential Organ Failure Score (SOFA) score have been found to aid in the prediction of delirium in the critically ill.

It has been demonstrated that pattern of secretion and concentration of melatonin are altered in critically ill patients (5). Melatonin release from the pineal gland is also decreased due to surgical stress and hence its potential use in postoperative delirium (6). Sepsis-associated delirium is a cerebral manifestation commonly occurring in patients with other infection-related organ dysfunctions and is caused by a combination of neuroinflammation and disturbances in cerebral perfusion (7). Procalcitonin is a helpful biomarker for early diagnosis of sepsis in critically ill patients (8).

Melatonin acts via melatonin receptors present in the suprachiasmatic nuclei (SCN) and promotes sleep by attenuating the wake-promoting signal from the SCN (9,10). Bioavailability of melatonin is excellent as demonstrated by supraphysiological level after exogenous supplementation (11).

The Confusion Assessment Method (CAM) is a diagnostic instrument used to screen and diagnose delirium in ICU. The CAM diagnostic algorithm is comprised of four components: (1) an acute (4) an altered level of consciousness. The diagnosis of delirium is based on the presence of both component 1 and 2, and either 3 and 4 (12).

Objective

The primary objective of the study was to determine the efficacy of exogenous melatonin in preventing delirium in postoperative patients admitted in ICU, as well as to compare the outcome by comparing the incidence of delirium and length of ICU stay in two groups. The secondary objective is to determine the association of delirium with severity of illness, which was measured in term of APACHE II and Procalcitonin level at the time of admission and daily SOFA scoring.

Methods

We performed a randomized, placebo-controlled study on postoperative patients admitted in our 20-bed tertiary level ICU. Inclusion criteria included adult postoperative patients requiring mechanical ventilation for more than 48 hours who were able to receive medication by the enteral route. Exclusion criteria included unwillingness to participate; sensitivity or history of allergic reaction to melatonin supplements; pregnancy; paralytic ileus; patients not expected to survive >48 hours; preexisting pathologies including cognitive dysfunction, dementia, psychiatric disorders or sleep disorders; history of head injury, substance abuse or withdrawal; and patients with hearing impairments.

Patients were randomized into two groups of 70 patients each with a sealed envelope randomization method. The study group received melatonin 5 mg via the enteral route at 8 pm every day and the control group received placebo (1 gm lactose powder) through a nasogastric tube until ICU discharge/transfer. APACHE II and procalcitonin (PCT) levels were recorded at admission, and SOFA scores were calculated daily. Delirium preventive measures including decreased light, noise, and regular patient orientation were applied uniformly in both groups. On the day of discharge/transfer the patients were evaluated using the CAM-ICU (Confusion Assessment Method) scale. The patients were categorized as “Delirious” or “Not Delirious” on the basis of the results from the CAM-ICU scale (12). Results were analyzed by comparing the incidence of delirium, length of ICU stay, APACHE II, SOFA Score and PCT value at the time of admission.

Results

A total of 140 adult post-operative patients transferred to the ICU who were ventilated more than 48 hours were evaluated. Table 1 contains the demographics of the study population.

Table 1: Between Group Comparison of Demographic Profile

Mean age of patients enrolled in the study was 38.70±11.56 years. Difference in age of patients in Group A (38.46±11.87) and Group B (38.94±11.33) was not statistically significant.

APACHE II scores did not differ at admission (Table 2).

Table 2: Between Group Comparison of APACHE II Score

Procalcitonin levels did not differ at admission (Table 3).

Table 3: Between Group Comparison of Procalcitonin (ng/ml)

Range of procalcitonin levels of patients of both the groups was 0.2-25.60 ng/ml. Though mean procalcitonin levels of patients of Group B (5.76±6.37 ng/ml) were found to be higher than that of Group A (4.81±6.60 ng/ml) yet this difference was not found to be significant statistically.

Duration of ICU stay was 4 to 27 days. Though mean ICU stay of patients of Group A (9.29±4.57 days) was higher than that of Group B this difference was not found to be significant statistically.

SOFA score of 56 patients of Group A and 55 patients of Group B could be assessed. Median SOFA score of patients of both the groups was 2.00, mean SOFA score of patients of Group A was 2.70±2.20 (range 0-9) while that of Group B was 2.53±1.63. On comparing SOFA score of patients of above two groups, difference was not found to be significant statistically.

CAM ICU score of 111 patients could be assessed. The majority of overall (68.5%) as well as Group A (76.8%) and Group B (60.0%) had negative CAM ICU scores. Though a higher proportion of Group B as compared to Group A had a positive CAM ICU score (40.0% vs. 23.2%), this difference was not found to be significant statistically.

There was no significant difference in the mortality of non-delirious patients.

Patients with delirium as compared to non-delirium had significantly higher values of APACHE-II (20.57±6.26 vs. 18.42±7.14) and significantly higher procalcitonin levels (5.84±6.25 vs. 3.42±6.57 ng/ml).

Table 4: Association of Delirium with Demographic Profile

 

Patients with delirium were found to be older as compared to non-delirium (41.57±9.99 vs. 35.87±11.81). This difference was found to be significant statistically. Proportion of females was higher among delirious as compared to non-delirious patients (54.3% vs. 47.4%), but this difference was not found to be significant statistically.

Delirium was less prevalent in Group A (16.6 percent) than Group B (31.4 percent), although the difference was not statistically significant. Melatonin administration did not significantly affect any of the other outcomes (p>0.05, all comparisons).

Discussion

Delirium is prevalent in all spheres of hospitalization, medical and surgical patients, more prominently in patients admitted to intensive care units. Owing to its multifactorial etiopathogenesis, multiple pharmacological and non-pharmacological methods have been described in various literatures for prevention and treatment of delirium.

Delirium is associated with various complications which may result in unfavorable outcomes. These complications may vary from minor complications like self-extubation, removal of catheters, weaning failure, increase length of ICU stay to increased mortality. Ely and coworkers(13) studied 275 mechanically ventilated medical ICU patients and determined that delirium was associated with a threefold increase in risk for 6-month mortality after adjusting for age, severity of illness, co-morbidities, coma, and exposure to psychoactive medications. The commonest factors significantly associated with delirium are dementia, increased age, co-morbidities, severity of illness, infection, decreased day to day activities, immobilisation, sensory disturbance, urinary catheterization, urea and electrolyte imbalance and malnutrition (14).

Frisk et al. (15) in 2004 conducted a study to assess the biochemical indicators of circadian rhythm of patients admitted in ICUs and found altered secretion patterns and reduction in the urinary metabolite of melatonin, 6-SMT (6-sulphatoxymelatonin). This indicated the possible disruption of this neurohormone in patients admitted in intensive care units. Andersen et al. (16)  concluded that exogenous melatonin could be utilized to alleviate preoperative anxiety in surgical and critical care patients and more importantly, to decrease the emergence of delirium in the early postoperative period. In our study, 140 adult post-operative patients were studied to establish the preventive role of melatonin in delirium. Aghakouchakzadeh et al. (17)  in 2017 conducted a comprehensive review to determine the effect of melatonin on delirium; they concluded that because exogenous melatonin can improve circadian rhythm and prevent delirium, melatonin supplementation could improve or manage delirium in the intensive care unit. Similarly, Yang et al. (18) in their review had found substantial preventative effects of melatonin on delirium .This investigation established a reason for the practice recommendations to recommend melatonergic medications for delirium prevention.

Out of 140 patients that we studied, 29 patients died during the trial, 35 were diagnosed with delirium and 76 had no delirium. Delirium was less prevalent in Group A (16.6 percent) than Group B (31.4 percent), although the difference was not statistically significant. This reduction is similar to the results found by Nishikimi et al. (19) in who found the melatonin agonist to be related to a trend toward shorter ICU stays, as well as significant reductions in the occurrence and duration of delirium in patients admitted to the ICU.

Sepsis and inflammation are important etiologies of delirium. Inflammatory biomarkers (procalcitonin and erythrocyte sedimentation rate) can be predictive of acute brain dysfunction and delirium. Hamza et al.  (20) procalcitonin was significantly higher in their delirious group in univariant (0.9±0.6 vs. 0.4±0.4ng/mL, P<0.001) and multivariate analysis (OR= 35.59, CI (7.73- 163.76)). Similarly, McGrane S et al. (21) conducted a study in 87 non-intensive care unit (ICU) cohorts and found that higher levels of procalcitonin were associated with fewer delirium/coma-free days (odds ratio (OR), 0.5; 95% confidence interval (CI), 0.3 to 1.0; P = 0.04). Our study showed similar results with significantly higher procalcitonin levels in patients with delirium than those without delirium (5.84±6.25 vs. 3.42±6.57 ng/ml).

The Acute Physiology and Chronic Health Evaluation II score (APACHE II) provides a classification of severity of disease and is particularly used in the ICU to predict mortality. In our study, APACHE II scores were calculated for each patient at their admission in the ICU. The range of APACHE-II score of patients enrolled was 6 to 38. Patients of Group A and Group B had comparable APACHE-II Score (21.07±8.17 vs. 21.84±7.81). Patients with delirium as compared to non-delirium had higher values APACHE-II scores (20.57±6.26 vs. 18.42±7.14). This was similar to the findings of Hamza SA et. al.(17), who, in their observational study of 90 patients, found not only have higher APACHE scores but also that the APACHE-II scores had significantly high diagnostic performance in discrimination of delirium (AUC = 0.877, P= <0.001).

Another clinically important score is the Sequential Organ Failure Score (SOFA) score used to sequentially assess the severity of organ dysfunction in critically ill patient ,  is an objective score that calculates the number and the severity of organ dysfunction in six organ systems (respiratory, coagulation , liver, cardiovascular, renal, and neurologic). In a prospective cohort study on 400 consecutive patients admitted to the ICU Rahimi-Bashar et al. (22) found the SOFA scores were significantly higher in those with delirium (7.37 ± 1.17) than those without delirium (4.93 ± 1.70). Similarly in our study, SOFA score of patients with delirium (4.49±1.63) was found to be significantly higher than that of non-delirium (1.75±1.37). Hence the elevated SOFA and APACHEII scores in the delirium can assist in identifying at-risk patients for delirium and hence allow interventions to improve outcomes. 

Aging is often associated with a disruption of the normal circadian cycle, which can also result in delirium. Thus, melatonin and its agonist may have a more significant influence on delirium in the elderly than in the young, Abbasi et al. (23) discovered that delirium is uncommon in a relatively young group. Thus, the relatively young age of our study sample and the enhancement of ICU care (such as decreased light, noise, and regular patient orientation) are the primary reasons for our study's low prevalence of delirium. Additionally, we found patients with delirium were older as compared to non-delirium (41.57±9.99 vs. 35.87±11.81).

As previously stated, the potential benefit of exogenous melatonin supplementation in reducing delirium incidence has been evaluated in non-ICU settings as well. While both the Sultan (24) and Jonghe (25) investigations examined whether melatonin may help postoperative patients avoid delirium, the de Jonghe study employed six times the amount of melatonin used in the Sultan study (3 mg versus 0.5 mg, respectively).

We suggest that individuals at risk of developing delirium, such as the elderly, should be investigated in future researches. Also, further studies are required comparing subgroups of medical, surgical, and trauma patients to determine which patients will benefit most from exogenous melatonin administration. Because plasma and urinary levels of melatonin are directly related to its concentration in the central nervous system, we also recommend monitoring melatonin levels in plasma or urine during the study and for follow-up to ascertain which subgroup of patients benefited most from exogenous melatonin supplementation to prevent delirium.

Conclusion

The study demonstrates there is decreased incidence of delirium in the patients who received exogenous melatonin, although this difference was statistically not significant (p=0.057). There was a statistically significant association of age with development of delirium (p=0.015). It has also been observed that the higher procalcitonin levels are associated with increased incidence of delirium (<0.001).

References

1. American Psychiatric Association A. Diagnostic and statistical manual of mental disorders. Washington, DC: American Psychiatric Association; 1980 Jan 1.
2. Maldonado JR. Delirium in the acute care setting: characteristics, diagnosis and treatment. Crit Care Clin. 2008 Oct;24(4):657-722, vii. [CrossRef] [PubMed]
3. Hshieh TT, Fong TG, Marcantonio ER, Inouye SK. Cholinergic deficiency hypothesis in delirium: a synthesis of current evidence. J Gerontol A Biol Sci Med Sci. 2008 Jul;63(7):764-72. [CrossRef] [PubMed]
4. Maldonado JR. Pathoetiological model of delirium: a comprehensive understanding of the neurobiology of delirium and an evidence-based approach to prevention and treatment. Crit Care Clin. 2008 Oct;24(4):789-856, ix. [CrossRef] [PubMed]
5. Olofsson K, Alling C, Lundberg D, Malmros C. Abolished circadian rhythm of melatonin secretion in sedated and artificially ventilated intensive care patients. Acta Anaesthesiol Scand. 2004 Jul;48(6):679-84. [CrossRef] [PubMed]
6. Can MG, Ulugöl H, Güneş I, Aksu U, Tosun M, Karduz G, Vardar K, Toraman F. Effects of Alprazolam and Melatonin Used for Premedication on Oxidative Stress, Glicocalyx Integrity and Neurocognitive Functions. Turk J Anaesthesiol Reanim. 2018 Jun;46(3):233-237. [CrossRef] [PubMed]
7. Atterton B, Paulino MC, Povoa P, Martin-Loeches I. Sepsis Associated Delirium. Medicina (Kaunas). 2020 May 18;56(5):240. [CrossRef] [PubMed]
8. Wacker C, Prkno A, Brunkhorst FM, Schlattmann P. Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet Infect Dis. 2013 May;13(5):426-35. [CrossRef] [PubMed]
9. Sack RL, Hughes RJ, Edgar DM, Lewy AJ. Sleep-promoting effects of melatonin: at what dose, in whom, under what conditions, and by what mechanisms? Sleep. 1997 Oct;20(10):908-15. [CrossRef] [PubMed]
10. Cajochen C, Kräuchi K, Wirz-Justice A. Role of melatonin in the regulation of human circadian rhythms and sleep. J Neuroendocrinol. 2003 Apr;15(4):432-7. [CrossRef] [PubMed]
11. Bellapart J, Appadurai V, Lassig-Smith M, Stuart J, Zappala C, Boots R. Effect of Exogenous Melatonin Administration in Critically Ill Patients on Delirium and Sleep: A Randomized Controlled Trial. Crit Care Res Pract. 2020 Sep 23;2020:3951828. [CrossRef] [PubMed]
12. Shi Q, Warren L, Saposnik G, Macdermid JC. Confusion assessment method: a systematic review and meta-analysis of diagnostic accuracy. Neuropsychiatr Dis Treat. 2013;9:1359-70. [CrossRef] [PubMed]
13. Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE Jr, Inouye SK, Bernard GR, Dittus RS. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004 Apr 14;291(14):1753-62. [CrossRef] [PubMed]
14. Ahmed S, Leurent B, Sampson EL. Risk factors for incident delirium among older people in acute hospital medical units: a systematic review and meta-analysis. Age Ageing. 2014 May;43(3):326-33. [CrossRef] [PubMed]
15. Frisk U, Olsson J, Nylén P, Hahn RG. Low melatonin excretion during mechanical ventilation in the intensive care unit. Clin Sci (Lond). 2004 Jul;107(1):47-53. [CrossRef] [PubMed]
16. Andersen LP, Gögenur I, Rosenberg J, Reiter RJ. The Safety of Melatonin in Humans. Clin Drug Investig. 2016 Mar;36(3):169-75. [CrossRef] [PubMed]
17. Aghakouchakzadeh M, Izadpanah M, Soltani F, Dianatkhah M. Are Melatonin and its Agonist the Natural Solution for Prevention of Delirium in Critically Ill Patients? A Review of Current Studies. Jundishapur Journal of Natural Pharmaceutical Products. 2017 Aug 31;12(3 (Supp)). [CrossRef]
18. Yang CP, Tseng PT, Pei-Chen Chang J, Su H, Satyanarayanan SK, Su KP. Melatonergic agents in the prevention of delirium: A network meta-analysis of randomized controlled trials. Sleep Med Rev. 2020 Apr;50:101235. [CrossRef] [PubMed]
19. Nishikimi M, Numaguchi A, Takahashi K, Miyagawa Y, Matsui K, Higashi M, Makishi G, Matsui S, Matsuda N. Effect of Administration of Ramelteon, a Melatonin Receptor Agonist, on the Duration of Stay in the ICU: A Single-Center Randomized Placebo-Controlled Trial. Crit Care Med. 2018 Jul;46(7):1099-1105. [CrossRef] [PubMed]
20. Hamza SA, Ali SH, ElMashad NB, Elsobki HS. Is there a Role for Procalcitonin in Delirium. Gerontol Geriatr Res. 2016;2(2):1010. [CrossRef]
21. McGrane S, Girard TD, Thompson JL, Shintani AK, Woodworth A, Ely EW, Pandharipande PP. Procalcitonin and C-reactive protein levels at admission as predictors of duration of acute brain dysfunction in critically ill patients. Crit Care. 2011;15(2):R78. [CrossRef] [PubMed]
22. Rahimi-Bashar F, Abolhasani G, Manouchehrian N, Jiryaee N, Vahedian-Azimi A, Sahebkar A. Incidence and Risk Factors of Delirium in the Intensive Care Unit: A Prospective Cohort. Biomed Res Int. 2021 Jan 8;2021:6219678. [CrossRef] [PubMed]
23. Abbasi S, Farsaei S, Ghasemi D, Mansourian M. Potential Role of Exogenous Melatonin Supplement in Delirium Prevention in Critically Ill Patients: A Double-Blind Randomized Pilot Study. Iran J Pharm Res. 2018 Fall;17(4):1571-1580. [PubMed]
24. Sultan SS. Assessment of role of perioperative melatonin in prevention and treatment of postoperative delirium after hip arthroplasty under spinal anesthesia in the elderly. Saudi J Anaesth. 2010 Sep;4(3):169-73. [CrossRef] [PubMed]
25. de Jonghe A, van Munster BC, Goslings JC, Kloen P, van Rees C, Wolvius R, van Velde R, Levi M, de Haan RJ, de Rooij SE; Amsterdam Delirium Study Group. Effect of melatonin on incidence of delirium among patients with hip fracture: a multicentre, double-blind randomized controlled trial. CMAJ. 2014 Oct 7;186(14):E547-56. [CrossRef] [PubMed]

Cite as: Gupta K, Singh VK, Arshad Z, Singh GP. Effect Of Exogenous Melatonin on the Incidence of Delirium and Its Association with Severity of Illness in Postoperative Surgical ICU Patients. Southwest J Pulm Crit Care Sleep. 2022;25(2):7-14. doi: https://doi.org/10.13175/swjpcc030-22 PDF 

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