Efficacy of intravenous immunoglobulin treatment in immunocompromised children with H1N1 influenza: a clinical observation

Background and Aims: The appropriate treatment of pandemic H1N1 influenza which was first identified in April 2009 in Mexico is insufficient especially for immunocompromised patients. We aimed to evaluate the features and prognostic factors of the
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  Efficacy of intravenous immunoglobulin treatment inimmunocompromised children with H1N1 influenza:a clinical observation Bahar Gokturk 1 , Sevgi Pekcan 2 , Sukru Nail Guner 3 , Hasibe Artac 4 , Sevgi Keles 3 , Mine Kirac 3 andIsmail Reisli 3 1 Department of Pediatric Immunology and Allergy, Konya Training and Research Hospital, Konya, Turkey2 Division of Pediatric Pulmonology, Department of Pediatrics, Necmettin Erbakan University Meram Medical Faculty, Konya, Turkey3 Division of Pediatric Allergy and Immunology, Department of Pediatrics, Necmettin Erbakan University Meram Medical Faculty, Konya, Turkey4 Division of Pediatric Allergy and Immunology, Department of Pediatrics, Selcuk University Medical Faculty, Konya, Turkey Abstract Background and Aims:  The appropriate treatment of pandemic H1N1 influenzawhich was first identified in April 2009 in Mexico is insufficient especially forimmunocompromised patients. We aimed to evaluate the features and prognosticfactors of the children with H1N1, especially immunocompromised ones, andwhether intravenous immunoglobulin G (IVIG) replacement could aid for a betteroutcome.  Methods:  Twenty-one hospitalized children with laboratory-confirmed H1N1were evaluated retrospectively. Data were extracted from files and electronicmedical records. Results:  The median age was 37 (1–216) months; 62% of them were under 5 yearsof ageand71.4%hadoneormoreunderlyingdisorders.Mainsymptomswerehighfever, cough, fatigue and vomiting. Lower respiratory tract manifestations wereseen in 66.6% of children. Mortality rate was 4.7%. The patient who died had thelowest lymphocyte (100/mm 3 ),thrombocyte (21 000/mm 3 ) and highest blood ureanitrogen (87 mg/dL) levels.Fifty-eight percent of evaluated patients had one of theprimary immunodeficiency disorders. Surprisingly, none of the six patients withprimary immunodeficiency who are on regular IVIG replacement needed intensivecare unit and died.Although median durations of cough, fever and hospitalizationwere lower, they did not change statistically according to get IVIG replacementregularly ( P   =  0.47, 0.97, 0.09, respectively). Conclusion:  Our study is important while it is the first one that shows the course of primary immunodeficient children with H1N1 infection who were on regular IVIGreplacement.A trial of high-dose IVIG may be a useful adjunctive therapy in severeH1N1 influenza, particularly in the immunocompromised patients.Please cite this paper as: Gokturk B, Pekcan S, Guner SN, Artac H, Keles S, Kirac Mand Reisli I. Efficacy of intravenous immunoglobulin treatment in immuno-compromised children with H1N1 influenza: a clinical observation.  Clin Respir J  2014; ••: ••–••. DOI:10.1111/crj.12209. Key words child – H1N1 influenza – immunodeficiency –intravenous immunoglobulin G Correspondence Bahar Gokturk, MD, Department of PediatricImmunology and Allergy, Konya Training andResearch Hospital, Meram, 42090 Konya,Turkey.Tel:  + 90 332 221 00 00Fax:  + 90 332 323 67 23email: gokturkbahar@yahoo.comReceived: 03 May 2014Accepted: 27 August 2014DOI:10.1111/crj.12209 Authorship and contributorship Bahar Gokturk and Sevgi Pekcan conceived ofthe study, participated in its design and draftedthe manuscript. Sukru Nail Guner performed thestatistical analysis and revised the manuscript.Hasibe Artac, Sevgi Keles and Mine Kirac revisedthe manuscript and contributed to its drafting.Ismail Reisli conceived of the study, participatedin its design and revised the manuscript. Allauthors read and approved the final manuscript. Ethics This study has been approved by the ethicscommittee at the Necmettin Erbakan UniversityMeram Medical Faculty, Konya, Turkey. Conflict of interest The authors have stated explicitly that there areno conflicts of interest in connection with thisarticle. Introduction Influenza virus belongs to the orthomyxovirus family of RNA viruses, and human disease is predominantly caused by types A and B. Type A virus is the mostvirulent and can easily mutate; many subtypes of typeA have been identified on the basis of the occurrence of surface glycoproteins, hemagglutinin (H) and neura-minidase (N). Three times in the past century, pan-demic influenza viruses have circulated globally and The Clinical Respiratory Journal  ORIGINAL ARTICLE 1 The Clinical Respiratory Journal (2014) • ISSN 1752-6981© 2014 John Wiley & Sons Ltd  have caused increased morbidity and mortality amongpersons who were not generally at risk for severe sea-sonal influenza (1–3). A new strain of an influenza Avirus subtype H1N1, referred to as the ‘novel H1N1’,first identified in Mexico in April 2009. The novelH1N1 virus has features of North American and Eura-sian swine, avian and human influenza viruses (4).This novel virus spread rapidly to all regions of Turkey after the first laboratory-confirmed case inTurkey on June 27, 2009. Between July 1, 2009 andJanuary 19, 2010, approximately 6.5 million peoplewere infected, 13 000 patients were hospitalized and656 persons died in Turkey due to 2009 pandemicH1N1 infection (5). Nearly half of the influenza-related deaths during the 1918–1919 pandemicoccurred among young (20–40 years of age) and pre-viously healthy adults for reasons that have never beenexplained adequately (6). The data concerning clinicalcourse and appropriate treatment of severe influenzaare insufficient for immunodeficient patients. Andalso, trials of new modalities of treatment are essentialfor the patients with acute respiratory distress syn-drome (ARDS) associated with influenza A infection.Here, we aimed to evaluate the clinical and laboratory features of the pediatric patients with the diagnosis of pandemic H1N1 and if intravenous immunoglobulinG (IVIG) replacement could aid for a better outcomeespecially for immunocomprimised patients. Materials and methods Data were collected from 21 children under 18 yearsold who were hospitalized at the pediatrics depart-ments of Selcuk University Meram Faculty of Medi-cine, a tertiary hospital, between October 31, 2009 andDecember 24, 2009 with the criteria for pandemicinfluenza A infection according to the World HealthOrganization (7) and Central of Centers for DiseaseControl and Prevention diagnosis criteria (8) andunderwent radiological examinations. Diagnosis of 2009 pandemic H1N1 influenza was confirmed by testing nasopharyngeal swabs using an reverse-transcriptase polymerase chain reaction assay atNational Influenza Reference Laboratory at AnkaraHıfzı Sıha Institutue,our national reference laboratory.The study was approved by the Institutional Review Board of our institution.Clinical and laboratory data were extracted fromfiles and electronic medical records. Age at diagnosis,sex, complaints at admission (fever, cough, myalgia,headache, fatigue, throat ache, runny nose, nasalobstruction,difficultyinbreathing,diarrhea,vomiting,abdominal ache, change in level of consciousness andconvulsion),underlyingdisordersthatwereconsideredasriskfactorsforsevereinfluenza[chroniclungdisease,asthma, cardiac disease, primary immunodeficiency disorders, secondary immunodeficiency (malignancy and use of immunosuppressive treatment), chronicrenal dysfunction, chronic neurological disorders,endocrinological disorders, hematological disordersand malnutrition], physical examination findings(tonsillopharyngitis, lymphadenopathy and dehy-dration), respiratory complications (rales, rhonchi,dyspnea, hypoxia, wheezing, pneumothorax andpneumomediastinum), necessity for pediatric inten-sive care unit (PICU), management and mechanicalventilation (MV),length of hospital and PICU stay,useand time of oseltamivir therapy, use of IVIG and mor-tality rate were recorded. Hypogammaglobulinemiawas defined as at least one of the major serum immu-noglobulin classes below 2 standard deviation (SD) of the age-defined norms. Primary immonodeficient/immunocompromised patients were accepted aspatients having an impaired immune responsivenesscaused by congenital immunodeficiency (9).The statistical analysis was done using SPSS version16.0 software (SPSS Inc., Chicago, IL, USA). Data arepresented as numbers (percentages), mean  ±  SD, ormedian (range) as appropriate. Categorical variableswere compared using the chi-square test or Fisher’sexact test, and differences in continuous variablesbetween groups were assessed using unpaired Stu-dent’s  t  -tests and the Mann–Whitney   U   for independ-ent samples.  P   values below 0.05 were consideredstatistically significant in all analyses. Results Nasopharyngeal swab specimens were obtained from35 patients who met criteria for pandemic influenza Ainfection.Twenty-oneof themwereH1N1positiveandevaluated retrospectively. Thirteen (61.9%) patientswere male. The median age of patients was 37 (1–216)months. Thirteen (61.9%) of them were under 5 yearsof age. Fifteen children (71.4%) had one or moreunderlyingdisordersincludingasthma( n  =  1),chroniclung disease ( n  =  5) (bronchiectasis, bronchopulmo-nary dysplasia, bronchiolitis obliterans), chronicneurological disease ( n  =  3) (epilepsy, hydrocephaly,Down syndrome, Tay–Sachs disease), malnutrition( n  =  3), autoimmune disease ( n  =  2) (autoimmunethyroiditis with thyroidectomy, autoimmune hemoly-tic anemia), congenital heart disease ( n  =  2) (ven-tricular septal defect), chronic renal disease ( n  =  1) Intravenous immunoglobulin G in H1N1  Gokturk  et al  . 2  The Clinical Respiratory Journal (2014) • ISSN 1752-6981© 2014 John Wiley & Sons Ltd  (glomerulonephritis secondary to IVIG infusion) andprimary immunodeficiency ( n  =  10) (suspected tran-sient hypogammaglobulinemia of infancy, hyper IgEsyndrome, adenosine deaminase deficiency, Bruton’sdisease, CD3 γ   deficiency, Chediak–Higashi syndrome)(Table 1).The symptoms and signs on admission are detailedin Table 2.The main symptoms were high fever,cough,fatigueandvomiting.Themainsignswererales(57%),hypoxemia (38%), pharyngitis/tonsillitis (33.3%) anddifficulty in breathing (33.3%). The median durationsof cough, hospitalization and fever were 3 (0–25), 5(1–20) and 2 (0–8) days, respectively. There was nodifference between age groups for these parameters.Two of the patients (9.5%) had severe neurologicalcomplications (change in the level of consciousness,convulsion).A 10-month-old girl who had both stuporand convulsion died.Blood cultures were taken for determining probablebacterial bloodstream infection in 10 children(47.6%). Coagulase-negative  Staphylococcus  was iso-lated in 3 (14.2%) children in blood cultures, and intwo of them the isolation was accepted as bacteremia.Most patients (76.1%) received oseltamivir. Themedian duration of oseltamivir therapy was 5 (1–10)days. The median time of initiation of oseltamivirtherapy after the onset of disease was 72 h (24–336),and 33.3% of children received oseltamivir within thefirst 48 h, 77.7% received oseltamivir within the first72 h of disease.No relation was found between mediantime of initiation of oseltamivir and hypoxia( P   =  0.96). Additionally, nearly all patients toleratedoseltamivir well. Median time of initiation of oseltamivir therapy was not statistically different forthe patients who had IVIG replacement therapy every 3 weeks when compared with the patients who did nothave regular IVIG replacement ( P   =  0.18).Eleven (52.3%) of the patients needed oxygensupport and four (19%) needed PICU. Only one(4.7%) patient needed MV and died. This 10-month-old girl with suspected transient hypogammaglobu-linemia of infancy and encephalitis presented withstatus epilepticus resistant to anti-epileptics, needed Table 1.  The features of patients with primary immunodeficiency and who had IVIG replacementNumber DX AD Age* Hx PICU MV Ex IVIG OIT†1 HIES (DOCK-8 mutation) AHA, BE, hydrocephaly, ISD 139  + − − −  R 722 HIES (mutation unknown) BA, BE 122  + − − −  R 3363 Late-onsetADA def.BA, BE, Ml 216  − − − −  R 1924 CD3 γ   def. BE, AT 86  − − − −  R 725 CHS (BMT) BA, ISD for GVHD 38  − − − −  R 726 Bruton’s disease None 132  − − − −  R 247 HG None 10  + + + +  SD 488 BE None 119  − − − −  3D 729 HG Tay–Sachs D. 18  + − − − −  2410 HG BPD, Ml 14  + − − − −  24 *Months.†Hours.AD, accompanying disorder; ADA, adenosine deaminase; AHA, autoimmune hemolytic anemia; AT, autoimmune thyroiditis with thyroidectomy; BA,bronchial asthma; BE, bronchiectasia; BMT, bone marrow transplantation; BPD, bronchopulmonary dysplasia; CHS, Chediak–Higashi syndrome; def.,deficiency; DOCK, Dedicator of cytokinesis; DX, diagnosis; Ex, exitus; GVHD, graft vs host disease; HG, hypogammaglobulinemia; HIES, hyperimmuno-globulinEsyndrome;Hx,hypoxia;ISD,immunosuppressivedrug;IVIG,intravenousimmunoglobulinG;Ml,malnutrition;MV,mechanicalventilation;OIT,oseltamivir initiation time; PICU, pediatric intensive care unit; R, regularly; SD, single dose (0.4 g/kg); 3D, totally 3 doses given in concomitant 3 days. Table 2.  Symptoms and signs of the patients with H1N1Symptom/sign Number/percentage (%)Fever 18/85.7Cough 18/85.7Fatigue 12/57Rale 12/57Vomiting 8/38Hypoxia 8/38Pharyngitis/tonsillitis 7/33.3Difficulty in breathing 7/33.3Diarrhea 5/23.8Wheezing 4/19Throat ache 4/19Rhonki 4/19Dehydration 4/19Headache 3/14.2Runny nose/nasal obstruction 2/9.5Severe neurological complications 2/9.5Abdominal ache 2/9.5Myalgia 2/9.5 Gokturk  et al  .  Intravenous immunoglobulin G in H1N1 3 The Clinical Respiratory Journal (2014) • ISSN 1752-6981© 2014 John Wiley & Sons Ltd  MV, PICU and died to whom IVIG (0.5 g/kg) wasreplacedatthe10thhourof admission,andoseltamivirwas started within 48 h after the onset of first com-plaints. She had hyponatremia (Na  =  129 mEq/L),hyperpotassemia (K  =  5 mEq/L), high C-reactiveprotein (CRP  =  23 mg/dL), procalcitonin (1.16 ng/mL), alanine aminotransferase (ALT  =  51 U/L),aspartate aminotransferase (AST  =  124 U/L), bloodure nitrogen (87 mg/dL), the lowest absolute lympho-cyte (ALC  =  100/mm 3 ) and platelet (PLT  =  21 000/mm 3 ) counts. Surprisingly, none of the six patientswith severe primary immunodeficiency who got IVIGevery 3 weeks died.Among the 17 patients that were examined, 10(58.8%) were found to have one of the primary immu-nodeficiency disorders (Table 1). Totally, eight patientshadIVIGreplacement.Amongthese,onlya10-month-old patient with suspected transient hypogammaglo-bulinemia of infancy and encephalitis presented withstatus epilepticus resistant to anti-epileptics, neededMV, PICU and died to whom IVIG (0.5 g/kg) wasreplacedatthe10thhourof admission.Anotherpatientwho was 119 months old and had bronchiectasia of anunknown cause had a total dose of 1.5 g/kg over 3consecutive days (0.5/kg per day for 3 days). He hadneutropenia (740/mm 3 ), lymphopenia (890/mm 3 ) andthrombocytopenia(101 000/mm 3 ),highAST(94 U/L),ALT (44 U/L) and CRP (46 mg/dL), but not immuno-deficiency. The remaining six patients had IVIGreplacement therapy every 3 weeks. It was noteworthy that none of these six patients required PICU and/orMV.Hypoxiawasdetectedin16.6%of thepatientswhohad IVIG replacement regularly, while it was seen in60% of the patients who did not have regular IVIGreplacement ( P   =  0.15). The median age of patientswho had IVIG replacement regularly was higher whencompared with the patients who did not have IVIGreplacement regularly [127 (38–216) months, 18.5(1–189)months,respectively,( P   =  0.003)].Themedianhospitalization time was 3 (2–6) days for the patientswho had IVIG replacement regularly and 5 (2–20) daysfor the patients who did not. Although median dura-tions of cough, fever and hospitalization were lower inpatientswhogotIVIGreplacementregularlycomparedwith the ones who did not have regular IVIG replace-ment, the variables were not statistically significant( P   =  0.47, 0.97, 0.09, respectively).There was no correlation between the levels of various laboratory values and the patient age groups.The mean white blood cell (WBC) count, hemoglobin(Hb), absolute neutrophil count (ANC), ALC andPLT counts were 8030  ±  5300/mm 3 , 11.1  ±  2.4 g/dL,2956  ±  1410/mm 3 , 1892  ±  1248/mm 3 and 241 000  ± 190 521, respectively. Lymphopenia, neutropenia andthrombocytopenia were detected in 38%, 9.5% and19% of the patients, respectively. Mean erythrocytesedimentation rate (ESR), CRP, procalcitonin, AST,ALT, serum sodium and serum potasium were26.2  ±  32 mm/h, 15.1  ±  12.6 mg/dL, 0.53  ±  0.47 ng/mL,72  ±  56 U/L,38.6  ±  33.5 U/L,132  ±  4.4 mEq/Land4.5  ±  0.4 mEq/L, respectively. While only one patientdied in our study group, laboratory parameters couldnot be evaluated in terms of being risk factors formortality. But the patient who died had the lowestlymphocyte (100/mm 3 ), thrombocyte (21 000/mm 3 )and highest blood urea nitrogen (BUN; 87 mg/dL)levels.Median ESR of the six patients who had IVIGreplacement regularly were significantly higher( P   =  0.03), ALC was lower ( P   =  0.01) and AST waslower ( P   =  0.05) when compared with the ones whodid not have regular IVIG replacement (Table 3). Themean ANC, PLT, Hb, CRP and Na levels were higher,and WBC, procalcitonin, AST, ALT, K and BUN levelswere lower in patients on regular IVIG replacementwhen compared with the ones who were not, but noneof the parameters were statistically different (Table 3). Discussion This study is the first one that shows the possible effi-cacyof IVIGreplacementinchildrenwithH1N1infec-tion and primary immunodeficiency. Although themortality rate, need for PICU and MV could not beevaluated while only one patient died, it was notewor-thy that none of the patients with severe immunodefi-ciency on regular IVIG replacement needed PICU,MVand died. New researches with larger number of patients are needed to demystify this subject.The most common symptoms at presentation arereported as fever, cough and respiratory problems inmost reports (10, 11). Similarly, in our study, fever andcough were the most common clinical signs (85.7%),followed by fatigue (57%). Lower respiratory tractmanifestations (respiratory distress, hypoxia, wheez-ing, rales, rhonki) were seen in 66.6% of children andwere similar to those reported by Bettinger  et al  . fromCanada but more than Çiftçi  et al  . from Turkey (10,11). Digestive symptoms tend to be more commonthan seasonal influenza infection, which is detected as23.8% diarrhea and 38% as vomiting in our study (12).Two of the patients (9.5%) had severe neurologicalcomplications (change in the level of consciousness,convulsion); the one who had both stupor and convul-sion died. Although the majority of fatal outcomes Intravenous immunoglobulin G in H1N1  Gokturk  et al  . 4  The Clinical Respiratory Journal (2014) • ISSN 1752-6981© 2014 John Wiley & Sons Ltd  have been related to pulmonary complications, in few series and in many case reports it is emphasized thatacute necrotizing encephalopathy should be relatedwith high mortality (13, 14). Randolph  et al  . foundthat mortality is particularly high in the children withchronic neurological disease and immune suppression.He also mentioned that secondary complicationsincluding myocarditis, encephalitis and clinical diag-nosis of early presumed methicillin-resistant  S. aureus co-infection of the lung were found as mortality risk factors (15). In other reports, bronchial asthma wasfound to be a significant risk factor for children withH1N1 (16, 17). Although we could not determine therisk factors which influence on mortality because of low numbers of patients, the mortality rate, need forPICU and MV, oseltamivir use rate, the rate of chronichealth condition, the distribution of the sex and ageswere similar with the literature (11, 15, 16).Among 17 patients that were examined, 10 (58.8%)were found to have one of the primary immunodefi-ciency disorders in our series. Six of them were takingIVIG replacement every 3 weeks. Only one of theimmunosuppressed patients with possible diagnosis of transient hypogammaglobulinemia of infancy andwho admitted with encephalitis died,although he got asingle dose of IVIG (0.4 g/kg). The encephalitis and a younger age of this patient were thought to be risk factors for mortality. Surprisingly, none of the six patients with severe primary immunodeficiency whogot IVIG replacement regularly needed PICU or MV,and none died. Median ESR of these patients weresignificantly higher when compared with the ones whodid not have regular IVIG replacement (43.7  ±  24.4 vs19.1  ±  14.8 mm/h, respectively,  P   =  0.03), which may be the result of their recurrent/chronic inflammationor IVIG replacement. The cause of their well-beingcould be due to almost enough level of anti-H1N1antibodies as a consequence of routine IVIG replace-ment.Until now,none of the reports mentioned aboutthe frequency and mortality rates for primary immu-nodeficient patients, and there are few reports thatevaluate the use of IVIG for H1N1 positive patients.Despite the fact that data regarding IVIG in severeH1N1 infections was limited, one study had reportedsignificant neutralizing activity of human IVIG prepa-rationsagainstthepandemicH1N1virus(18).Anotherobservation by researchers was the association of low total immunoglobulin subclass levels, particularly IgG2, in both pregnant and non-pregnant H1N1 2009patients who developed respiratory failure (19).Chong et al  . from Malaysia treated a 59-year-old male patientwith ARDS successfully with a combination of doubledoseof oseltamivirand0.4 g/kg/doseIVIgGfor5 days,which was started on day 13 of illness and on day 6 of oseltamivir administration (20). In 2003, Morishimafrom Japan reported that a combination of antivirals,high-dose gamma-globulin, steroid pulse therapy,high-dose antithrombin III, headcooling and plasmaexchange could reduce the mortality of pediatricpatients with influenza-associated encephalopathy  Table 3.  Laboratory features of the patientsLaboratory parametersRegular IVIG( + ) Regular IVIG( − ) P  ( n  =  6) ( n  =  15)WBC (#/mm 3 ) 5045  ±  1913 9062  ±  5099 0.18Hb (g/dL) 12.3  ±  1.1 11.4  ±  1.6 0.67PLT (#/mm 3 ) 313 300  ±  99 050 310 400  ±  185 690 0.91ANC (#/mm 3 ) 3065  ±  1562 5138  ±  4000 0.56ALC (#/mm 3 ) 1095  ±  801 3060  ±  1696 0.01ESR (mm/h) 43.7  ±  24.5 19.1  ±  14.8 0.03CRP (mg/dL) 48.7  ±  24.6 21.4  ±  23.9 0.14PRO (ng/mL) 2.40  ±  5.44 2.48  ±  6.50 0.21AST (U/L) 33.3  ±  14.6 68.3  ±  41.8 0.05ALT (U/L) 18.0  ±  6.5 32.0  ±  22.2 0.15Glu (mg/dL) 91.0  ±  2.8 117.0  ±  30.4 0.07Na (mEq/L) 135.4  ±  3.4 135.6  ±  6.3 1K (mEq/L) 4.02  ±  0.79 4.46  ±  0.38 0.16BUN 31.6  ±  28.3 25.3  ±  23.3 0.67 ALC, absolute lymphocyte count; ALT, alanine aminotransferase; ANC, absolute neutrophil count;AST, aspartate aminotransferase; BUN, blood urea nitrogen; CRP, C-reactive protein; ESR, erythro-cyte sedimentation rate; Glu, glucose; IVIG, intravenous immunoglobulin G; Hb, hemoglobin;K, potassium; Na, sodium; PLT, platelet; PRO, procalcitonin; WBC, white blood cell.Gokturk  et al  .  Intravenous immunoglobulin G in H1N1 5 The Clinical Respiratory Journal (2014) • ISSN 1752-6981© 2014 John Wiley & Sons Ltd
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