Final Nepas Journal 30-1.indd -1-Journal of Nepal Paediatric Society January-June, 2010/Vol 30/Issue 1 Original Article January-June, 2010/Vol 30/Issue 1 Is Low Hemoglobin Level a Risk Factor for Acute Lower Respiratory Tract Infections? Malla T1, Pathak OK2, Malla KK3 1Dr. Tejesh Malla, MBBS, MD, Assistant Professor, 2 Dr. Om K Pathak, MBBS, Medical Officer, 3Dr. Kalpana K Malla, MBBS, MD, Associate Professor. All from the Department of Paediatrics, Manipal College of Medical Sciences, Pokhara, Nepal. Address for correspondence: Dr. Tejesh Malla, E-mail: tejeshmalla@hotmail.com Abstract Objective: This prospective study was conducted to evaluate whether a low hemoglobin level, was a risk factor for Acute Lower Respiratory Tract Infections (ALRTI) in children. Methods: 150 Children of all age groups who came to the outpatient department and those admitted for ALRTI were included in the study. Age and sex-matched 140 children, not having any respiratory illness, were taken as control. The study period was from March 2006 - March 2007. Detailed clinical and laboratory evaluation of the enlisted patients was done. All were subjected to detail investigations. Results: Radiological evidence of pneumonia was present in 70 (50 %) children.Hyperinflated lungs were seen in 40 (29%) and was normal in 30 (21.4%) cases. Blood culture was positive in 14 (10%) children of study group and none among control group. Klebsiella was the commonest organism isolated 6 (4.2%) in blood culture positive cases. The mean Hemoglobin (Hb) level of study group was 9.88 gm% and it was 12 gm% in control group.96 (68.6%) of study group and 30 (21.42%) of control group had anemia. Of the anemic children, 79 (82.3%) in study group had iron deficiency, and 17 (17.7%) had normocytic normochromic anemia. These values were 18 (33.3%) and 36 (66.6%) respectively for control group. Low hemoglobin level was a risk factor (p<0.001) ALRTI. Conclusion: Anemic children were 3.2 times more susceptible to ALRTI compared to the control group and and iron deficiency anemia was predominating. Supplemental iron therapy may reduce the incidence of ALRTI. Prevention of anemia, due to whatever etiology is also essential. Key words: ALRTI, anemia, hemoglobin. Introduction Anemia is a major nutritional global problem of immense public health signifi cance, affecting persons of all ages, sex and economic group. It is ranked as the commonest chronic malady of mankind affecting approximately 30% i.e. 1500 million people all over the world. Iron defi ciency anemia in children occurs most frequently between the age of 6 months to 3 years1, the age when repeated infection occurs. On an average, children below 5 years of age suffer about 5-6 episodes of ALRTI per year2. With this view the present study was conducted to see if children with iron defi ciency anemia were at higher risk of ALRTI. Methods This prospective study was carried out for a period of one year from March 2006 – March 2007 in pediatric department of Manipal Teaching Hospital, Pokhara. A total of 290 (150 cases and140 controls) children from 1 month to 5 years of age attending out patient department and those hospitalized were studied. Controls were age and sex matched children not having respiratory problems. The inclusion criteria for cases were children with fever, cough, and fast respiratory rate, chest indrawing as per WHO criteria, and ronchi or crepitations on auscultation. The exclusion criteria was children suffering from other systemic illnesses like -2-January-June, 2010/Vol 30/Issue 1 Journal of Nepal Paediatric Society Congenital heart disease, tuberculosis (any evidence plus Montaux test positive cases) and Protein Energy Malnutrition (PEM > Grade III as per Indian Academy of Pediatrics (IAP) classifi cation). Children who already received antibiotic from outside were also excluded from the study. The purpose of the study was explained to the parents or guardians. Then consent was taken from parents or guardians before they were subjected to investigations. The investigations in both case and control included; complete blood count (CBC) with a peripheral smear, blood culture and sensitivity test, and X-ray chest, serum iron and serum iron binding capacity. Serumferritin level was not done. Syanmeth method by colorimeter was used to identify Hb level. Hemglobin level < 10 gm % will be considered low in this study. Data were analysed using SPSS 10.0 by logistic multinomial regression analysis. Results Out of 290 children 150 were cases among which 10 were Mantoux positive hence was excluded from the study. Therefore the fi nal fi gure was 140 (99 males and 41 females) cases and 140 (94 males and 46 females) controls. Among the cases 10 (8 males and 2 females) were less than 2 months, 69 (43 M and 26 F) were inbetween 2months – 1 year and 61 ( 48M and 13F ) were above 1 year. Similarly for control group the distribution was 10 (6M/4F), 50(30M/20F), and 80 (58M/22F) were ≤2months, 2mo-1year and >1 year respectively. (Table1). Fever, cough and shortness of breath was main clinical features in the cases whereas fever, pain abdomen diarrhea, vomiting, seizures was main clinical features in the control group (Table 2). Radiological evidence of pneumonia was present in 70 (50 %) children, hyperinfl ated lungs in 40 (29%) cases and normal in 30 (21.4%) cases (Fig 1). Out of 40 children who had hyperinfl ated lung fi elds 20 (50%) had a history of recurrent wheeze ( fi g.2) and 10 ( 25%) gave a positive family history of asthma. Blood culture was positive in 14 (10 %) children of study group (Table 3) and none among control group. Among the culture positives klebsiella was isolated in 6 (4.2%), and growth of staphylococcus, streptococcus pneumoniea, acintobacter and E.coli was noted in 2 (1.43%) cases each. The mean Hb level of study group was 9.88 gm% and it was 12 gm% in control group.96 (68.6%) of study group and 30 (21.42%) of control group had anemia. Of the anemic children, 79(82.3%) in study group had iron defi ciency, with mean MCV 64 (fl ),Mean MCH 17pg,MCHC 25gm/dl,Mean S. Iron 35μg/dL,Mean TIBC 390μg/dL.17 (17.7%) had normocytic normochromic anemia. These values were 18 (33.3%) [With mean MCV 68.7 (fl ), Mean MCH 15pg, Mean MCHC 27gm/dl, Mean S. Iron 35μg/dL, Mean TIBC 350μg/dL] and 36 (66.6%) respectively for control group (Table 4). There were 72 cases of bronchopneumonia among which 62 (86%) of them were anemic whereas rest 68 were wheeze associated ALRTI (bronchiolitis & recurrent wheeze ) of which 34 (50%) were anemic.(Table 5). Descriptive data regarding multivariate logistic regression analysis showing the risk factor of ALRTI. Table 7 reveals the montaux positive cases which were excluded from the study. Table 1: Age and Sex distribution of cases and control Sex Age Total ≤2 months >2mo-1yr >1 -5 year Case ; Male=99 (70.7%) Female=41(29.3%) 8 2 43 26 48 13 140 Total 10 69 61 140 Control: Male= 94 (67%) Female=46 (32.8%) 6 4 30 20 58 22 140 Total 10 50 80 140 -3-Journal of Nepal Paediatric Society January-June, 2010/Vol 30/Issue 1 Table 2: Symptoms and signs at presentation Symptoms Case Control N (n=140) Percentage N(n=140 ) Percentage Fever 135 96.42% 114 81.42% Cough 140 100% 8 5.71% Shortness of breath 81 57.85% 4 2.85% Convulsion 10 7.14% 30 21.42% Vomiting 29 20.71% 77 55% Diarrhea 10 7.14% 52 37.14% Noisy breathing 50 35.71% 0 0% Poor feeding 80 57.14% 60 42.85% Chest pain 4 2.85% 0 0% Irritable 20 14.28% 30 21.42% Fast breathing 100 71.42% 0 0% Delayed development 0 0% 6 4.28% Headache 0 0% 2 1.42% Pain abdomen 0 0% 35 25% Sore throat 0 0 % 24 17% Signs Chest indrawings 120 85.71% 0 0% Ronchi 70 50% 0 0% Crepitations 60 42.85% 0 0% Pyoderma 0 0% 4 2.85% Dehydration 5 3.57% 35 25% Table 3: Blood culture of cases and control Case (n=140) Control (n=140) Blood culture Number Percentage Number Percentage No growth Growth Klebsiella Staphylococcus S. Pneumniea Acintobacter E.coli 126 14 6 2 2 2 2 90 % 10% 4.2% 1.43% 1.43% 1.43% 1.43% 140 0 100% 0% 0 10 20 30 40 50 Ser 0% 0% 0% 0% 0% 0% pneum ies1 50 monia h 0% 50% yperinflation 29% 29% norma 21.40% 21.4 al % 40% Series1 Fig. 1: Radiological fi ndings of cases -4-January-June, 2010/Vol 30/Issue 1 Journal of Nepal Paediatric Society Table 4: Hemogram of Cases and Control. Case (n=140) Control (n=140) Hemoglobin Number Percentage Number Percentage Mean Hb 9.88gm % 12gm % Hemoglobin ≤10gm%± >10gm% 96 44 68.6%) 31.4% 54 86 38.6% 61.4% Anemia type MH* NN** 79 17 82.3% 17.7% 18 36 33.3% 66.6% MH anemia NN anemia MH anemia NN anemia Mean MCV(fl )*** 64 80 68.7 79 Mean MCH(pg)**** 17 25 15 27 Mean MCHC(gm/dl)***** 25 32 27 34 S. Iron 35μg/dL 95 35 μg/dL 100 Mean TIBC+ 390 μg/dL 268 350 μg/dL 270 Note : Anemic± = Hb< 10gm/dl (Normal Hb in < 2mo 9 – 14 gm/dl and > 2months 11.5-15.5gm/dl)3 MH*= Microcytic Hypochromic, NN**=Normocytic Normochromic, MCV***=Mean Corpuscular Volume ( 1month- 6 yrs = 76- 88(fl ),4MCH****=Mean Corpuscular Hemoglobin ( 1month- 6 yrs= 24-30 (pg ),4 MCHC*****= Mean corpuscular Hemoglobin Concentration ( 1month- 6 yrs=30-36gm/dl),4 S.Iron (infants =100-400 μg/dL and above Infancy =250-400 μg/dL)3,TIBC+ -Total Iron Binding Capacity (all age =22-184 μg/dL )3 50% 50% h N h/o wheezing No Wheezing Fig. 2: Histrory of wheezing 0 5 10 15 20 1 7 13 19 25 31 37 43 49 55 61 67 73 79 85 91 97 103 109 115 121 127 133 139 children in case and control H b le ve l i n gm % Series1 Series2 Fig. 3: Graph showing range of Hb in case and control -5-Journal of Nepal Paediatric Society January-June, 2010/Vol 30/Issue 1 Discussion Acute lower Respiratory tract infection (ALRTI) is a leading cause of mortality in children below 5 years of age in developing countries5. Hence it is important to control the risk factors to prevent deaths from ALRTI. Along with many risk factors like low birth weight, lack of breast feeding, severe malnutrition, smoke, cooking fuel6, low hemoglobin may also be a risk factor. Present study was carried out to prove this fact.There were 140 cases (M=99 & F= 41) and 140 controls (M=94&F=46) among which in cases maximum children were between 2month – 1 year.This signifi es that ALRTI is most common in age group 2month to 1 year. This is the time when a child starts having low hemoglobin levels and also this is the period of adding supplemental feed which may be inadequate and inappropritate. The reasons for higher number of males may be gender biasness by the parents to bring them for hospital care. Sign symptoms of patient had usual presentation of ALRTI. These patients came to us only after 4-5 days of illness or when the child became more ill as with less illness people of this region do not visit hospital. Radiologically evidence of pneumonia was higher 70 (50 %) than hyperinfl ated lungs (bronchiolitis, recurrent wheeze) 40 (29%).This Table 5: Low Hemoglobin with type of ALRTI Bronchopneumonia (N= 72) Wheeze associated LRTI bronchiolitis / recurrent wheezing (N= – 68 ) Number percentage Number percentage Hemoglobin ≤10gm% >10gm% 62 10 86.0 % 13.9 % 34 34 50 % 50 % Total =140 72 100% 68 100% Table 6: Multivariate Logistic Regression Analysis Showing the Risk factor of ALRTI Parameters OR 95% CI Signifi cance HB≤10 5.6 2.7-11.7 df=1, p<0.001 S.Iron 15.6 8.2-29.6 df=1, p<0.001 TIBC 1.7 0.86-3.4 df=1, p= 0.119 C.I: Confi dence interval, OR: Odds Ratio,df:degree of freedom, LRTI- Lower Respiratory Tract Infection. Table 7: History, Clinical fi nding and CXR of Mantoux positive cases. Cases with Mantoux positive 1 2 3 4 5 6 7 8 9 10 Recurrent ARI + + - + - + + + + + ESR > 50mm/1st hr + + + + + + + + + + Contact with TB - - + + + _ _ - + - Weight loss + + + + - - + + + + CXR – compatible with tuberculosis + + - - - - - - + + Gastric lavage for AFB _ _ _ _ _ _ _ _ _ _ Crofton, Horne and Miller scoring > 7 9 9 8 10 8 7 8 9 9 8 may indicate that low hemoglobin has higher risk for pneumonia than bronchiolitis. Table 5 reveals that among pneumomia cases 86% were anemic whereas only 50% cases were anemic among bronchiolitis cases.There was no specifi c golden criterion to differentiate bacterial (pneumonia) or viral (bronchiolitis) ALRTI but ill looking child, CRP positive,neutrophilic leukocytosis,blood culture positive was considred bacterial infection and viral infection were assessed clinically and leucopenia was considered. Literature related to this fi nding was not available. It was observed that 20(50%) children with hyperinfl ated lung fi elds had a history of wheeze and 10 ( 25%) gave a positive family history of asthma. This maybe due to the fact that bronchiolitis is more prone to occur if there is a genetic predisposition or has a history of Atopy rather than low hemoglobin. These population was not excluded from the study as they had features of secondary infection clinically with high fever, ill looking, not feeding well and biochemically with either neutrophilic leukocytosis or CRP positive. Blood culture showed growth in only 10 % of cases and klebsiella was most common (4.2%) organism isolated. In this study Hb ≤ 10gm/dl was considered anemia (Normal Hb = -6-January-June, 2010/Vol 30/Issue 1 Journal of Nepal Paediatric Society <2mo 9-14gm/dl and > 2months -11.5 – 15.5gm/dl)3. Mean Hb level in this study was 9.58 gm% for cases &12gm% for Control group. Ramakrishnan K, Harish PS in their study found that anemic children were 5.75 times more susceptible to LRTI7 which was 3.2 times in this study. Several risk factors for developing ALRTI had been reported in different studies. Baskaran et al8 in their study in children between 3-5 years had found 83% with pneumonia had hemoglobin less than 11 g/dL. In this study microcytic and hypochromic picture was seen in maximum children (82.3%). In another study of iron defi ciency anemia and respiratory infection by De-Silva A et al9, an over all prevalence of anemia was found in 52.6%. The role of low hemoglobin level per se, as a risk factor for developing ALRTI are reported only in few literatures7. They had found that reduced hemoglobin level due to whatever etiology was a signifi cant risk factor for developing ALRTI. Unlike those studies here it was found that low hemoglobin due to Iron defi ciency anemia was the main cause for ALRTI. Iron defi ciency anemia was detected based on low MCV(normal=76-88 fl ), low MCH(Normal=24-30 pg ), low MCHC(Normal=30- 36gm/dl), low S.Iron [Normal=infants 100-400 μg/dL and above Infancy 250-400 μg/dL] and increased TIBC[ Normal =all age=22-184 μg/dL]. Serum ferritin level was not done due to unavailability of this test and ferritin level is not reliable in cases with infection as it increases probably as acute phase protein10. If you look at the normal function of Hemoglobin it facilitates oxygen (O2) and carbon dioxide (CO2) transport. It caries and inactivates nitric oxide (NO) and also play the role of a buffer11. Hemoglobin in the blood is mainly responsible for stabilizing the oxygen pressure in the tissues 12. Therefore quantitative and/or qualitative reduction in Hb, may adversely affect the normal functions. Iron is principally required for haemoglobin synthesis.13 Intestinal iron absorption is related to erythropoietic requirements, although the regulatory mechanism(s) remain unknown. The usual source of iron in the lung is serum iron which is derived from catabolised erythrocytes and absorbed iron13. Probably it may be the reason for low hemoglobin level found to be as a serious risk factor for developing ALRTI. Further studies including other risk factors like low birth weight, lack of breast feeding, severe malnutrition, smoke, cooking fuel etc along with low hemoglobin should be considred as future perspective. Conclusion To conclude Hb was a risk factor for LRTI (p<0.001). Iron defi ciency anemia was the main cause detected. Anemia was responsible for pneumonia more than bronchilitis.Iron supplementation in age group 1month to 5 years may reduce the incidence of LRTI and prevention of anemia, due to whatever etiology is also essential. The limitation of this study is that other variables were not considered in this study. It is diffi cult to correlate the one point prevalence of pneumonia with anaemia as the control group could present with pneumonia within another few months. Only way to see is to follow a group of children with normal and low haemoglobin over a period of time for an episode of pneumonia. Acknowledgements: We thank all the children who had participated in this study. A special thanks to Dr. Praveen shrestha who had helped with data collecton. Funding: None Confl ict of Interest: None References 1. DeMaeyer EH, Adiels - Tegman M. The prevalence of anemia in the world. World Health Statistics 1985, 38, 302-316. 2. Wald ER. Recurrent and non Resolving Pneumonia in 20 children. Sem Resp Infect 1993; 8: 46-58. 3. Michael A.Pesce. Reference Ranges for Laboratory Tests and procedures. In Richard E. Behrman, Robert Kleigman, Hal B Jenson, ed. Nelson Text Book of Pediatrics. 18th ed. Philadelphia; Saunders, 2008: 2944. 4. Forfar & Arneil. Text Book of Pediatrrics 5th Edition 1998; Campbell A.G.M. & McIntosh N, BPC Wheatons Ltd; Exeter; 1939. 5. Rasmussen Z,Pio A, Enarson P. Case Management of Childhood Pneumonia in Developing Countries: Relevant Research and Current Initiatives. Int J Tuber Lung Dis 2000:4;807-827 6. Behrman S. Epidemiology of Acute Respiratory Infection in Children of Developing Countries. Rev Infect Dis 1991: (suppl): S454-S462. 7. Ramakrishnan K, Harish PS. Hemoglobin Level as a Risk Factor for Lower Respiratory Tract Infections. Indian J Pediatr. 2006:73:10:881-883. 8. Bhaskaran P, Madhavan Nair K, Balakrishnan N. Serum transferrin receptors in children with respiratory infections. Eur J Nutr. 2003; 57: 75-80. 9. De-Silva A, Atukorola S, Weerasinghel. Iron supplementation improves iron status and reduces morbidity in childrenwith or with out URTI. Am J Clin Nutr 2003; 77: 234-241. -7-Journal of Nepal Paediatric Society January-June, 2010/Vol 30/Issue 1 10. Ryan TP, Krzesicki RF, Blakeman DP, et al. Pulmonary Ferritin: Differential Effects of Hyperoxic Lung Injury on Subunit mRNA Levels. Free Radic Biol Med 1997;22:901-908 11. William F Ganong. Gas transport between the lungs and the tissues. Review of Medical Physiology. 22nd ed. New York; Mc Graw-Hill, 2005: 666-669 12. Guyton & Hall. Effect of hemoglobin to ‘Buffer’ the tissue PO2. Text Book of Medical Physiology. 11th ed. Philadelphia; Saunders, 2006: 507-508. 13. Fernando Mateos, Jeremy H Brock, José Luis Pérez-Arellanoa. Iron metabolism in the Lower Respiratory Tract. Thorax. 1998; 53:594-600.