IJCP Nov 2012

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Volume 23, Number 6

November 2012, Pages 301-360

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Clinical Study

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Original Study

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Drug Review

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Clinical Practice

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IJCP Group of Publications Dr Sanjiv Chopra Prof. of Medicine & Faculty Dean Harvard Medical School Group Consultant Editor Dr Deepak Chopra Chief Editorial Advisor

Volume 23, Number 6, November 2012

from the desk of group editor-in-chief 305 Multivitamins may Lower Cancer Risk in Men

Dr KK Aggarwal CMD, Publisher, Group Editor-in-Chief Dr Veena Aggarwal MD, Group Executive Editor

IJCP Editorial Board

review article 307 Management of Respiratory Tract Infections

Obstetrics and Gynaecology Dr Alka Kriplani Dr Thankam Verma, Dr Kamala Selvaraj Cardiology Dr Praveen Chandra, Dr SK Parashar Paediatrics Dr Swati Y Bhave Dr Balraj Singh Yadav Dr Vishesh Kumar

Courses Available:

Diabetology Dr Vijay Viswanathan Dr CR Anand Moses, Dr Sidhartha Das Dr A Ramachandran, Dr Samith A Shetty

317 A Phase IV Clinical Case Study to Evaluate the

Efficacy and Safety of a Polyherbal Health Drink (HiOwna-Jr) on Growth, Health and Cognition in Children

Spectroscopic Approach

328 Bacteriological Spectrum of Surface Wound

Infections and their Antimicrobial Susceptibility Pattern in a Rural Medical College Hospital in West Bengal

Neurology Dr V Nagarajan

Munmun Das, Hirak Jyoti Raj

drug review

Journal of Applied Medicine & Surgery Dr SM Rajendran Anand Gopal Bhatnagar Editorial Anchor

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S Gunasekaran, TS Renuga Devi, A Ramanand, M Madurai Veeran

original study

Dermatology Dr Hasmukh J Shroff

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Dilip V Deshpande, Padmanabha Rugvedi

324 Efficacy of Erypro on Anemic Patients: A

Dentistry Dr KMK Masthan Dr Rajesh Chandna

Nephrology Dr Georgi Abraham

Pawan Mangla, KK Aggarwal

clinical study

ENT Dr Jasveer Singh

Gastroenterology Dr Ajay Kumar

KK Aggarwal

335 Esomeprazole and Levosulpiride in Management

of GERD

Ajay Kumar

Advisory Bodies Heart Care Foundation of India

Clinical Practice

Non-Resident Indians Chamber of Commerce & Industry World Fellowship of Religions

This journal is indexed in IndMED (http://indmed.nic.in) and full-text of articles are included in medIND databases (http://mednic.in) hosted by National Informatics Centre, New Delhi.

340 Neonatal Conjunctivitis: The Joint Responsibility

of Obstetricians, Pediatricians and Ophthalmologists

Harpal Singh Jhagta

case report Published, Printed and Edited by Dr KK Aggarwal, on behalf of IJCP Publications Ltd. and Published at E - 219, Greater Kailash, Part - 1 New Delhi - 110 048 E-mail: editorial@ijcp.com

343 A Rare Case of Chorangiosis of Placenta:

from the desk of group editor-in-chief

An Important Placental Sign of Neonatal Morbidity and Mortality

Printed at IG Printers Pvt. Ltd., New Delhi

Dr KK Aggarwal

Padma Shri and Dr BC Roy National Awardee Sr. Physician and Cardiologist, Moolchand Medcity, New Delhi President, Heart Care Foundation of India Group Editor-in-Chief, IJCP Group and eMedinewS Chairman Ethical Committee, Delhi Medical Council Director, IMA AKN Sinha Institute (08-09) Hony. Finance Secretary, IMA (07-08) Chairman, IMA AMS (06-07) President, Delhi Medical Association (05-06) emedinews@gmail.com http://twitter.com/DrKKAggarwal Krishan Kumar Aggarwal (Facebook)

Sandhya Mittal, Anupama Goel, Bal Krishan Taneja, Meenu Puri

347 Kikuchi Disease in an Uncommon Age and Site

Š Copyright 2012 IJCP Publications Ltd. All rights reserved.

The copyright for all the editorial material contained in this journal, in the form of layout, content including images and design, is held by IJCP Publications Ltd. No part of this publication may be published in any form whatsoever without the prior written permission of the publisher.

Shalinee Rao, Amudha Janaki, CN Sai Shalini, Sandhya Sundaram

practice guidElines 350 ACP Releases Guideline on Intensive Insulin

Editorial Policies

Therapy in Hospitalized Patients

The purpose of IJCP Academy of CME is to serve the medical profession and provide print continuing medical education as a part of their social commitment. The information and opinions presented in IJCP group publications reflect the views of the authors, not those of the journal, unless so stated. Advertising is accepted only if judged to be in harmony with the purpose of the journal; however, IJCP group reserves the right to reject any advertising at its sole discretion. Neither acceptance nor rejection constitutes an endorsement by IJCP group of a particular policy, product or procedure. We believe that readers need to be aware of any affiliation or financial relationship (employment, consultancies, stock ownership, honoraria, etc.) between an author and any organization or entity that has a direct financial interest in the subject matter or materials the author is writing about. We inform the reader of any pertinent relationships disclosed. A disclosure statement, where appropriate, is published at the end of the relevant article.

Multivitamins may Lower Cancer Risk in Men

photo quiz 351 Bubbles on the Skin Following Renal Transplant

medilaw 353 Registration of IVF Lab under PNDT Act

MC Gupta

A

fter about 11 years, the daily multivitamin use resulted in an 8% reduction in total cancer incidence in men according to the results of a very large randomized trial by John Michael Gaziano, MD, MPH from Harvard at the Annual American Association for Cancer Research (AACR) Frontiers in Cancer Prevention Research meeting and also published in JAMA. Cancer mortality also went in 12% reduction.

Previous studies have reported conflicting results. As reported by Medscape Medical News, two studies evaluating the association of multivitamins and breast cancer found opposite results - one study found an increased risk while the other found that multivitamins decreased the risk. Another study reported more neutral results, in that multivitamin use had no influence on the risk for common cancers, cardiovascular disease or overall mortality.

lighter reading 354 Lighter Side of Medicine

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Indian Journal of Clinical Practice, Vol. 23, No. 6, November 2012

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Original Study

review article

Management of Respiratory Tract Infections pawan mangla*, kk aggarwal**

Abstract Respiratory tract infections, both upper and lower, are a common and important cause of morbidity and mortality worldwide.

The most common respiratory pathogens include Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis.

Empiric antibiotics are often prescribed for these infections. However, the respiratory pathogens are becoming increasingly resistant to currently used antibiotics such as amoxicillin-clavulanate (Amoxy-Clav). Hence, there is a perceived need for a broad-spectrum antibiotic, which is effective against the common respiratory tract pathogens. Cefaclor is an oral semi-synthetic second-generation cephalosporin with a broad-spectrum activity against bacteria, including resistant strains, responsible for most community-acquired infections such as respiratory tract infections. It has proven efficacy in the management of respiratory tract infections, both upper and lower and has continued to maintain its efficacy in despite several years of widespread use.

It is also well-tolerated.

Keywords: Respiratory tract infections, broad-spectrum antibiotic, cefaclor

R

espiratory tract infections are common and perhaps the most reported of all human infections. They are traditionally divided into two: Upper respiratory tract infections and lower respiratory tract infections. Often, these infections are mild and sometimes self-limiting. Hence, many of these infections are ignored by patients. Respiratory tract infections are a common and important cause of morbidity and mortality worldwide.1 They are one of the most common reasons that patients seek medical attention2 and given time constraints and perceived patient expectations many consultations end with an antibiotic prescription.3

PC/DT PYR/BRI/70/2012/Oct

About 13 million under-five children die every year in the world; 95% of them in developing countries.

One-third of total deaths are due to acute respiratory tract infections. It is estimated that at least 300 million episodes of acute respiratory tract infections occur in India every year; out of these, about 30-60 millions are moderate-to-severe acute respiratory tract infections.

While every 6th child in the world is Indian, every 4th child who dies, comes from India.4 An average adult has 2-4 episodes/year and a child has 6-8 episodes/year.5 Around 20% of the mortality due to infectious

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*Chest Physician Moolchand Medcity, New Delhi **Senior Physician and Cardiologist Moolchand Medcity, New Delhi

diseases in India is caused by lower respiratory tract infections.6 Treatment with an appropriate antimicrobial agent significantly decreases the bacterial burden, and may reduce the risk of the patient progressing to a more severe infection.

However, the common respiratory tract pathogens, including Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, are becoming increasingly resistant to currently used antibiotics7 such as amoxicillin-clavulanate (Amoxy-Clav). So, when making treatment choices, it is important for practitioners to consid足 er the most commonly encountered pathogens as well as the potential for resistance to ensure that the appropriate antimicrobial is prescribed. Since, nearly all community-acquired and healthcare-associated respiratory infections are treated empirically, there is need for a broad-spectrum antibiotic, which is effective against the common respiratory tract pathogens.

Microbiology of respiratory tract A large number of bacterial species colonize the upper respiratory tract (nasopharynx). The nares (nostrils) are always heavily colonized, predominantly with Staphylococcus epidermidis and corynebacteria, and often with Staphylococcus aureus, this being the main carrier site of this important pathogen. The healthy sinuses, in contrast are sterile. The pharynx (throat)

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review article is normally colonized by streptococci and various gram-negative cocci. Sometimes pathogens such as S. pneumoniae, Streptococcus pyogenes, H. influenzae and Neisseria meningitidis colonize the pharynx. In contrast, the lower respiratory tract (trachea, small bronchi and alveoli) is usually sterile, mainly because of the efficient cleansing action of the ciliated epithelium, which removes the pathogens. If the respiratory tract epithelium becomes damaged, as in bronchitis or viral pneumonia, the individual may become susceptible to infection by pathogens such as H. influenzae or S. pneumoniae descending from the nasopharynx.8

Some common bacterial diseases of the lower respiratory tract ÂÂ

Some common bacterial diseases of the upper respiratory tract ÂÂ

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Rhinosinusitis includes illnesses with predominantly nasal symptoms (including the common cold, nasopharyngitis and sinusitis) and high fever. The common etiopathogens in acute bacterial rhinosinusitis are S. pneumoniae and H. influenzae; occasionally, M. catarrhalis and S. aureus.9 Suppurative complications include orbital cellulitis and intracranial extension of infection.10 Pharyngitis describes illnesses when sore throat is most prominent (including tonsillitis).9 Pharyngotonsillitis caused by Group A b-hemolytic streptococci (GABHS) is one of the most common infections of childhood.11 Clinically, it presents as pain that may be associated with headache, fever and general malaise. Tonsillar or pharyngeal exudate, tender cervical lymphadenopathy and recent exposure to streptococcal throat infection are most useful in predicting bacterial infection.

A useful clinical prediction rule found that streptococcal infection was present in 50% of children if three of the following features were positive: Fever higher than 38°C, tonsillar swelling or exudates, tender cervical lymphadenopathy and absence of cough.9 Otitis media defines illnesses with predominantly middle ear symptoms. Best regarded as a spectrum of disease, it includes otitis media with effusion (OME, acute otitis media [AOM] without perforation [AOMwoP], AOM with perforation [AOMwiP] and chronic suppurative otitis media [CSOM]).9 S. pneumoniae, H. influenzae and M. catarrhalis are the most common bacterial isolates from the middle ear fluid of children with AOM.12 The symptoms of AOM include otalgia, ear-rubbing, fever, irritability, restless sleep, diminished appetite and excessive crying; since none is sensitive or specific, these symptoms do not help in distinguishing AOM from a respiratory tract infection.13

Indian Journal of Clinical Practice, Vol. 23, No. 6, November 2012

ÂÂ

Acute bronchitis is one of the most common conditions encountered in clinical practice. It is a self-limited inflammation of the bronchi due to upper airway infection. Patients with acute bronchitis present with a cough lasting >5 days (typically 1-3 weeks), which may be associated with sputum production. Acute bronchitis should be distinguished from chronic bronchitis, a condition in patients with chronic obstructive pulmonary disease distinguished by a cough for at least three months in each of two successive years.14 It can usually be distinguished from other acute respiratory infections by the predominance of cough, often accompanied by other respiratory and constitutional symptoms, and the absence of findings suggestive of pneumonia.15 It is one of the most common infections reported in children under five years of age, and is a leading cause of hospitalization.16 Acute bronchitis is generally caused by upper respiratory infections; approximately 90% are viral in origin and 10% are bacterial.17 Bacteria that may cause acute bronchitis include: S. pneumoniae, M. catarrhalis, H. influenzae (nontypeable), Chlamydia pneumoniae, Mycoplasma species. The most common bacterial pathogen that causes lower respiratory tract infections in children of all age groups is S. pneumoniae.

Community-acquired pneumonia (CAP) is defined as an infection of the lung parenchyma that is not acquired in a hospital, long-term care facility or other recent contact with the healthcare system.

It has traditionally been classified as typical, usually caused by S. pneumoniae, or as atypical, caused by M. pneumoniae, Chlamydophila pneumoniae (formerly Chlamydia pneumoniae) and Legionella species.18 S. pneumoniae is the most common pathogen in moderate-to-severe CAP and accounts for upto 60% of all bacteremic pneumonia.19 CAP manifests clinically as cough, sputum, localized physical signs on chest auscultation and fever.20

Smokers’ Cough Many cigarette smokers have a chronic cough, but rarely seek medical advice for this as they suppose the irritant effect of cigarette smoke to be the cause of their cough. A change in the pattern or characteristics of their cough, such as an increase in intensity (usually after an upper respiratory tract infection), or accompanying hemoptysis may force a smoker to seek medical attention. A chest radiograph is mandatory

in such a case.21 There is a direct relation between the incidence of chronic bronchitis and the number of cigarettes smoked. As the airflow obstruction becomes more severe, the incidence of cough increases.22

Management of lower respiratory tract infections ÂÂ

Acute bronchitis: Symptomatic treatment with antitussives or protussives or bronchodilators is indicated.26 Antibiotics are usually not prescribed for acute bronchitis; however, those patients with chest signs who are very unwell, are older (>55 years), have comorbidities or smoke may benefit from antibiotics.27

ÂÂ

CAP: CAP requires prompt and effective antibacterial treatment and conventional therapy for patients hospitalized with CAP has typically been parenteral antibacterial therapy for 7-10 days.28 The Indian Chest Society/Joint National College of Chest Physicians (India) (ICS/NCCP[I]) recommendations state that antibiotic should be administered as early as possible; timing is more important in severe CAP. Therapy is directed towards coverage of the most commonly isolated organism, S. pneumoniae. Recommended antibiotics are oral macrolides or oral b-lactams for outpatients with comorbidities. Fluoroquinolones are not recommended as empiric treatment.6

Management of upper respiratory tract infections ÂÂ

ÂÂ

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Acute bacterial rhinosinusitis (ABRS): Recent Infectious Diseases Society of America (IDSA) clinical practice guideline for ABRS in children and adults recommend that empiric antimicrobial therapy be initiated as soon as the clinical diagnosis of ABRS is established. A b-lactam agent rather than a respiratory fluoroquinolone is recommended for initial empiric antimicrobial therapy of ABRS.10 Pharyngitis: GABHS pharyngitis is usually self-limited and resolves within a few days, even without treatment.

Indications of antibiotic treatment are acute symptom relief, prevention of suppurative and nonsuppurative complications and to reduce communicability.

Penicillin is the treatment of choice.

Cephalosporins have been suggested to be more effective against GABHS. Higher rates of GABHS eradication and shorter courses of therapy with cephalosporins are beneficial.

Current US treatment guidelines recommend macrolides (erythromycin and azithromycin) for patients with penicillin allergy. But, erythromycin has gastrointestinal (GI) side effects; also, macrolide resistance is increasing among GABHS isolates, likely because of azithromycin overuse.23 Otitis media: Treatment goals include symptom resolution and reduction of recurrence.12 The management of AOM also includes an assessment of pain and the appropriate analgesic treatment, if pain is present.24 Empiric treatment should target the most commonly isolated bacteria in AOM: S. pneumoniae, nontypeable H. influenzae and M. catarrhalis.25 Antibiotics are recommended for all children younger than six months, for those six months to two years of age when the diagnosis is certain, and for all children older than two years with severe infection. In children with mild symptoms, observation is an acceptable approach.12 The American Academy of Pediatrics/American Academy of Family Physician (AAP/AAFP) guidelines also view compliance as important in selecting an antimicrobial for children.25

Cefaclor, a broad-spectrum b-lactam antibiotic Cefaclor is an orally effective semi-synthetic secondgeneration cephalosporin with a b-lactam ring-base structure. Cefaclor has demonstrated activity against a wide range of organisms in vitro.29

Mechanism of Action Cefaclor is a bactericidal antibiotic. It binds to penicillinbinding proteins (PBP) inside the bacterial cell wall and inhibits synthesis of bacterial cell wall resulting in cell lysis and death.

Clinical Pharmacology After oral administration of single dose, about 95% of cefaclor is absorbed. Peak serum concentration is attained about one hour after dosing in fasting subjects.

Cefaclor is well-absorbed when given with or without food. However, the peak concentration achieved is 50-75% of that observed in fasting subjects when taken after meals. The serum half-life of cefaclor in healthy subjects is averages around one hour and is independent of dosage form. After oral administration, cefaclor is excreted unchanged in the urine.30

Antimicrobial Spectrum Cefaclor has in vitro activity against a wide range of organisms causing community-acquired infections. It

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Cefaclor lacks antitubercular activity, unlike fluoroquinolones, so, it is particularly useful when diagnosis is in doubt especially in a country like India, where tuberculosis is very prevalent.

Acute Streptococcal Pharyngitis Short-course therapy with cefaclor is an effective alternative treatment to conventional regimens, with potential for better compliance. Clinical cure and bacteriological eradication was recorded in 92.8% and 92.6% of patients in Groups A and B, respectively after cefaclor treatment (25 mg/kg/b.i.d.) for a 5- or 10days.35 Studies have shown that the risk of relapse in patients treated with Amoxy-Clav is greater than with cefaclor; it is also associated with greater incidence of GI adverse events.

In a comparative study of cefaclor versus Amoxy-Clav in tonsillopharyngitis, the relative risk of relapse in patients treated with Amoxy-Clav was 2.6 greater compared to cefaclor. Also, there were significantly higher rates of GI adverse events in group treated with Amoxy-Clav (29.89%) compared to cefaclor (16.84%).36 A 10-day treatment with cefaclor (20 mg/kg/day) is a clinically and bacteriologically effective treatment for children with GABHS pharyngotonsillitis comparable to Amoxy-Clav (25 mg/kg/day), but much safer in terms of GI side effects. Significantly more relapses and recurrences were observed on follow-up in the AmoxyClav-treated group than in the cefaclor-treated group (relapse rate 21.28% vs 15.56%, p < 0.02, recurrence

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10.64% vs 6.66%, p < 0.002) (Fig. 1). Also, childrentreated with Amoxy-Clav reported higher rates of GI adverse events.11 In an earlier study, cefaclor 25 mg/kg b.i.d. had similar efficacy as Amoxy-Clav 15 mg/kg t.i.d. (cure rate, 91.9% and 90.5%, respectively) and was more effective than erythromycin 15 mg/kg t.i.d. (cure rate, 76.8%) for the treatment of pediatric patients with acute pharyngotonsillitis.37 The twice-daily dosing ensures good patient compliance.

Azithromycin and cefaclor were compared for the treatment of streptococcal pharyngitis/tonsillitis, or sinusitis in an open multicenter study. On days 11-15, a total of 308 patients with pharyngitis/tonsillitis were clinically evaluable (152 azithromycin patients and 156 cefaclor patients). In the azithromycin group, 94% of patients showed a satisfactory clinical response compared with 97% in the cefaclor group. When patients who had been classed as clinically cured or improved and in whom the baseline pathogen had been eradicated were assessed at Days 25-30, there was recurrence of the S. pyogenes infection in 5/105 (5%) azithromycin group patients and 4/108 (4%) cefaclortreated patients.38

Acute Otitis Media AOM is the most frequent respiratory tract infection of infancy and childhood. The most common causative pathogens include S. pneumoniae, H. influenzae and M. catarrhalis; hence, antibiotic therapy should target against these isolates.29 Cefaclor is active against most bacteria-producing AOM, including ampicillin-resistant H. influenzae.39 Moreover, cefaclor is readily absorbed and distributed to middle ear effusions. The levels obtained were above the minimal inhibitory concentration (MIC) values of most strains of respiratory pathogens.40

ÂÂ

Clinical success (clinical cure + improvement) at the end of therapy was significantly more in cefaclor arm: 98% with cefaclor versus 85% with Amoxy + Clav.

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Bacteriological eradication was seen in 95% of patients in cefaclor group and 78% of patients in Amoxy + Clav group.

im

e

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Maternal satisfaction

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Figure 1. Comparative study of cefaclor vs Amoxy-Clav in pharyngotonsillitis in children showing higher percentage of relapses and recurrence with Amoxy-Clav.

SM

Recurrence

20

Ce

Relapse rate

11

P-

0

Acceptance (with pleasure/without problems) Refusal/Resentment

26 16

llin

5

Cefaclor is a well-tolerated and effective antibacterial option for AOM in children.41 It was equally effective as cefuroxime axetil42 and clarithromycin43 and was more effective than cefixime or cefprozil.44 A multicenter study reported that cefaclor was superior to the combination of Amoxy + Clav in efficacy and tolerability in AOM. Cefaclor and Amoxy-Clav significantly improved all the signs and symptoms after a 10-day treatment period. But, between-thegroup comparisons showed that the reduction in most of the symptoms was significantly more in cefaclor arm versus Amoxy-Clav arm.29

67 56

55

TM

6.66

74

60

ici

10.64 10

81 73

ox

15

89

Am

15.56

100 90 80 70 60 50 40 30 20 10 0

lor

20

Its expanded-spectrum of activity, ability to achieve adequate concentrations in tissues, suitability for twicedaily dosing and proven tolerability make it a good alternative to agents traditionally used in AOM.29

fa c

Amoxy-Clav Cefaclor

21.28

Ce

25 Percentage (%)

is active in vitro against many gram-positive aerobes, gram-negative aerobes and selected anaerobic bacteria, including S. aureus, S. pneumoniae, S. pyogenes and H. influenzae (including ampicillin-resistant strains).31 The action of cefaclor against S. pneumoniae is superior.

Cefaclor is the most active antibiotic against strains of H. influenzae, and is also more active than cephalexin and cephradine against non-b-lactamase-producing strains of Escherichia coli, Klebsiella species and Proteus mirabilis.32 The in vitro activity of cefaclor was compared with that of cephalexin and cephradine by Gillett et al in another study. Cefaclor was the most active of the oral agents against H. influenzae (especially nonb-lactamase-producing strains).

It was also significantly more active against N. gonorrhoeae and the Enterobacteriaceae.33 Compared to cephradine and cephalexin, cefaclor was less resistant to staphylococcal penicillinase.34

Patient compliance (%)

review article

Figure 2. Comparative study showing variation in acceptance of common oral antibiotic suspensions; cefaclor was the most palatable.

‘pleasure’ or ‘without problems’ versus 60, 55 and 20% for amoxicillin, trimethoprim/sulfamethoxazole and cefuroxime axetil, respectively, whereas ‘resentment’ or ‘refusal’ was reported in 11, 16, 26 and 56%, respectively (p < 0.0001). Mothers reported to be generally ‘satisfied’ or ‘extremely satisfied’ with the drug in 89, 81, 74 and 67% with cefaclor, amoxicillin, trimethoprim/sulfamethoxazole and cefuroxime axetil, respectively (Fig. 2). Data from the study suggest that cefaclor suspension was the most palatable and thus better patient compliance could be expected.48

A retrospective study of 201 children was done to evaluate the efficacy and side effects of amoxicillin and cefaclor in the treatment of AOM and recurrent AOM. There were 456 episodes of AOM; of these, 245 episodes were treated with amoxicillin with an efficacy of 91%, while 211 episodes were treated with cefaclor with an efficacy of 97%.45 Compared to amoxicillin, cefaclor has been shown to be a better option in the chemoprophylaxis of recurrent AOM. In the 87 courses of chemoprophylaxis with cefaclor for recurrent otitis media, the efficacy was found to be 53%; while amoxicillin was found to be effective in 30% of the 33 patients studied.45 It is also useful in the prophylaxis of recurrent AOM in HIV-infected children. Cefaclor reduced the number of AOM episodes in 100% of cases.46 In a meta-analysis, adverse events were observed in a statistically significant lower percentage in the cefaclortreated patients compared to other antibiotics: 13.3% versus 19.4%.47

The most likely causative bacteria in outpatients include S. pneumoniae, M. pneumoniae, H. influenzae and Chlamydophila pneumoniae. M. pneumoniae, C. pneumoniae and Legionella spp., sometimes grouped as atypical organisms.49 The exact causative organism is not identified in many patients with CAP, so treatment is usually empiric.18 The activity of cefaclor against these pathogens has been demonstrated in several studies.

Palatability of oral antibiotic suspensions is important and is an important factor in determining compliance in children. The acceptance of and compliance with oral antibiotic suspensions commonly used in Israel was examined in a study; 546 children received one of the following drugs: Amoxicillin (n = 222); cefaclor (n = 142); cefuroxime axetil (n = 107); trimethoprim/ sulfamethoxazole (n = 75). Seventy-three percent of the cefaclor group reported acceptance of the drug with

Ahmed et al evaluated the antimicrobial activity of cefaclor against 466 isolates of respiratory tract pathogens. They found that of the 163 S. pneumoniae, 87 M. catarrhalis and 216 H. influenzae isolates, >95% isolates were susceptible to cefaclor. The study concluded that resistance of respiratory tract pathogens to cefaclor is very low. The MIC90 of cefaclor against these pathogens was <2 µg, which indicates that cefaclor would be effective in >90% of cases infected

In a comparative study, 100 patients with otitis media were clinically evaluated at end of therapy (11-15 days); of these, 52 patients were in the azithromycin group and 48 received cefaclor. Ninety percent of azithromycintreated patients and 96% of cefaclor patients were classified as responding satisfactorily.38

Community-acquired Pneumonia

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review article with these bacteria.50 Cefaclor has been demonstrated to be effective against b-lactamase-producing H. influenzae resistant to ampicillin.51 Against both penicillinase- and nonpenicillinase-producing strains of S. aureus, cefaclor was at least three times as active as cephradine at 2 µg/ml and at least one and a half times as active as cephalexin at this concentration in an in vitro study. At 2 µg/ml, cefaclor inhibited all b-lactamase-positive and -negative strains of H. influenzae at the generally recommended inoculums of 104 CFU/ml in contrast to cephalexin and cephradine, which required substantially greater concentrations to achieve the same order of activity and which were also considerably affected by Haemophilus b-lactamase.34

92.6% (50/54 isolates) for the cefaclor treatment group.

No cefaclor-treated patients were considered clinical failures at their end of therapy evaluations. The overall incidence of side effects was 18.9% for azithromycinand 12.1% for cefaclor-treated patients.53 The Infectious Diseases Society/American Thoracic Society (IDS/ATS) guidelines on the management of CAP in adults recommend that patients should be switched from intravenous (IV) to oral therapy when they are hemodynamically stable and improving clinically, are able to ingest medications and have a normally functioning GI tract.54

Cefaclor has comparable efficacy but a better tolerability profile than cefdinir in the treatment of CAP. A multicenter study compared the efficacy and safety of 10- day treatment with cefaclor (500 mg thrice-daily) and cefdinir (300 mg twice-daily) in treatment of CAP. The microbiological eradication rates at the test-of-cure visit were 93% and 92% for the evaluable patients treated with cefaclor and cefdinir, respectively. Patients treated with cefdinir had higher incidence of diarrhea than with cefaclor, 13.7% versus 5.3%, respectively (Fig. 3).52

Cefaclor is useful in the treatment of acute exacerbations of chronic bronchitis in cigarette smokers (n = 106) as demonstrated in a study. H. influenzae was the most common bacterial species isolated in the sputum (23%), followed by S. pneumoniae, S. aureus , K. pneumoniae and B. catarrhalis, while mixed forms were present in 22.6% of cases and other pathogens in 4.7%. Cefaclor (500 mg) was given orally thrice-daily for 7-16 days.

It was seen that 75.5% of patients were cured and 17.0% improved. These results illustrate that the spectrum of activity of cefaclor covers all the most likely pathogens encountered in smokers.59

Cefaclor is an effective oral antibiotic as switch over therapy in management of CAP. In a study, 95 patients were randomized to receive either a ‘conventional’ course of IV antibiotic therapy with cefamandole 1 g IV every 6-hour for one week, or an abbreviated course of IV therapy with cefamandole (1 g IV every 6-hour for 2 days) followed by oral therapy with cefaclor (500 mg every 8-hour for 5 days). Patients who received early oral therapy had shorter hospital stays (7.3 vs 9.71 days, p = 0.01), and a lower total cost of care ($2953 vs $5002, p < 0.05). The authors concluded that early transition to an oral antibiotic like cefaclor after an abbreviated course of IV therapy in CAP is substantially less expensive and has comparable efficacy to conventional IV therapy.55

Fifty-one patients admitted to hospital with severe exacerbations of chronic bronchitis entered a doubleblind trial of treatment with cefaclor (500 mg t.d.s.; n = 26) compared with amoxicillin (500 mg t.d.s.; n = 25) for duration of one week. The two drugs were comparable as regards clinical outcomes. The high prevalence of opportunistic colonizing organisms persisted at follow-up (48%) three weeks later with a significant excess of new organisms (Enterobacter cloacae, Klebsiella species and Candida species) present in sputum in the amoxicillin-treated patients. Cefaclor may be less damaging to normal flora than amoxicillin with a consequently reduced risk of colonization and superinfection of the respiratory tract with resistant gram-negative organisms and yeasts.60

Acute Bronchitis

Conclusion

Percentage (%)

In a randomized, double-blind study carried out in 28 centers, azithromycin (500 mg single dose on Day 1, followed by 250 mg once-daily on Days 2-5) was compared with cefaclor (500 mg t.i.d. for 10 days) in the treatment of acute bacterial pneumonia in 119 patients.

The clinical cure rates of azithromycin and cefaclor were 46.9% and 41.0%, respectively; improvement was seen in an additional 46.9% of azithromycintreated patients and in 59.0% of the cefaclor group.

The overall satisfactory clinical response was 97.3% for azithromycin patients and 100% for cefaclor patients.

The bacteriological eradication rate was 80.4% (37/46 isolates) for the azithromycin treatment group and

100 90 80 70 60 50 40 30 20 10 0

93

92

Cefaclor

Cefdinir

13.7 5.3 Microbiological eradication rate

Adverse events (Diarrhea)

Figure 3. Treatment of CAP showing comparable efficacy but better tolerability profile of cefaclor vs cefdinir.

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Switch from Intravenous to Oral Therapy

Cefaclor penetrates well into bronchial mucosa as demonstrated in a study. The mean bronchial cefaclor concentration after 250 mg was 3.78 μg/g (range 2.1-5.8 μg/g), after 500 mg 4.43 μg/g (range 2.0-7.1 μg/g) and after 1,000 mg 7.73 μg/g (range 5.0-12.7 μg/g).56 The resistance of respiratory tract pathogens to cefaclor has been reported to be very low. MIC90 of cefaclor against all three common respiratory tract pathogens is <2 μg, which indicates that cefaclor would be effective in >90% of cases infected with these bacteria.50 In an earlier study too, 87 strains of S. pneumoniae isolated during three winter seasons from the blood of children with acute lower respiratory tract infection showed 100% sensitivity to cefaclor as compared to 31% resistant to cotrimoxazole and 39% resistance to chloramphenicol.57 The Alexander Project, an international multicenter study monitoring trends in the antimicrobial susceptibilities of communityacquired lower respiratory tract pathogens to a range of antimicrobial agents. Out of 818 isolates of

M. catarrhalis 82% were b-lactamase producers and >90% isolates were susceptible to cefaclor.58

ÂÂ

ÂÂ

ÂÂ

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Respiratory tract infections are one of the commonest reasons for a visit to a family physician, and given time constraints and perceived patient expectations many consultations end with an antibiotic prescription.

Treatment with an appropriate antimicrobial agent significantly decreases the bacterial burden, and may reduce the risk of the patient progressing to a more severe infection.

When making treatment choices, it is important for practitioners to consid­er the most commonly encountered pathogens as well as the potential for resistance to ensure that the appropriate antimicrobial is prescribed.

The bacterial species most commonly isolated from patients with respiratory tract infections include S. pneumoniae, H. influenzae and M. catarrhalis.

Since nearly all community-acquired and

ÂÂ

ÂÂ

ÂÂ

ÂÂ

ÂÂ

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healthcare-associated respiratory infections are treated empirically, there is need for a broadspectrum antibiotic, which is effective against the common respiratory tract pathogens.

Cefaclor is an oral semi-synthetic secondgeneration cephalosporin, effective against various respiratory pathogens.

It has proven efficacy in the management of respiratory tract infections, both upper and lower and has continued to maintain its efficacy in despite several years of widespread use.

The incidence of resistance among respiratory pathogens to Amoxy-Clav is rising; it is also frequently associated with GI side effects, which may hinder patient compliance. Cefaclor is a better alternative to Amoxy-Clav as it is safer in regard to GI side effects and also does not exhibit resistance to most common respiratory pathogens.

The relative risk of relapse in patients with respiratory tract infections treated with AmoxyClav is greater compared to cefaclor.

Factors that contribute to the efficacy and tolerability of cefaclor include its molecular stability, activity against the most prevalent gram-positive and gramnegative respiratory tract pathogens, rapid absorption, >90% bioavailability and good penetration into respiratory mucosa. It is also well-tolerated. The twice-daily dosing ensures good patient compliance.

Cefaclor lacks antitubercular activity, unlike fluoroquinolones, so, it is particularly useful when diagnosis is in doubt especially in a country like India, where tuberculosis is very prevalent.

References 1. Nweze EI, et al. Asian Pac J Trop Dis 2012:2(1):18-23.

2. Liu HH, et al. J Fam Pract 2008;57(2 Suppl Managing): S12-8.

3. Naidoo KT, et al. CME 2004;22(4):200-3.

4. Prajapati B, et al. National J Commun Med 2011;2(2): 255-9.

5. Prajapati B, et al. Healthline 2012;3(1):16-20.

6. Gupta D, et al. Lung India 2012;29(Suppl 2):S27-S62.

7. Brunton S. J Fam Pract 2005;54(4):357-64.

8. Todar K. The bacterial flora of humans. Todar’s Online Textbook of Bacteriology. Available at: http:// textbookofbacteriology.net/normalflora_3.html.

9. Morris PS. Pediatr Clin North Am 2009;56(1):101-17.

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review article 10. Chow AW, et al. Clin Infect Dis 2012;54(8):e72-e112.

32. Knothe H. Infection 1979;7 Suppl 6:518-26.

11. Haczyński J, et al. Med Sci Monit 2003;9(3):PI29-35.

33. Gillett AP, et al. Postgrad Med J 1979;55 Suppl 4:9-11.

12. Ramakrishnan K, et al. Am Fam Physician 2007;76(11): 1650-8.

34. Bill NJ, et al. Antimicrob Agents Chemother 1977;11(3): 470-4.

13. McWilliams CJ, et al. Can Fam Physician 2011;57(11): 1283-5.

35. Esposito S, et al. Infez Med 2000;8(4):227-33.

14. File TM Jr. Acute bronchitis in adults. Available at: www. uptodate.com.

36. Haczyński J, et al. Med Sci Monit 2001;7(5):1016-22.

37. Esposito S, et al. Clin Ther 1998;20(1):72-9.

15. Aagaard E, et al. Infect Dis Clin North Am 2004;18(4): 919-37; x.

38. O’Doherty B. J Antimicrob Chemother 1996;37 Suppl C:71-81.

16. Fleming DM, et 2007;8(4):415-26.

39. Iancu TC, et al. Isr J Med Sci 1983;19(11):998-1000.

al.

Expert

Opin

Pharmacother

17. Carolan PL. Pediatric bronchitis. Available at: http:// emedicine. medscape.com/article/1001332.

18. Watkins RR, et al. Am Fam Physician 2011;83(11): 1299-306.

19. Torres A, et al. Pyogenic bacterial pneumonia and lung abscess. Chapter 32. In: Mason: Murray and Nadel’s Textbook of Respiratory Medicine. 5th edition, Elsevier: Saunders 2010:p.709.

40. Ernstson S, et al. Acta Otolaryngol Suppl 1985;424:7-12.

41. Catania S, et al. Infez Med 2004;12(4):259-65.

42. Turik MA, et al. J Chemother 1998;10(4):306-12.

43. Gooch WM 3rd, et al. Pediatr Infect Dis J 1993;12(12 Suppl 3):S128-33.

44. Kafetzis DA. Eur J Clin Microbiol Infect Dis 1994;13(10): 857-65.

45. Perry BP, et al. Ear Nose Throat J 1995;74(12):840-4.

20. McIvor RA. Can Fam Physician 2009;55(1):15-6, 19-21.

46. Zuccotti G, et al. J Int Med Res 2001;29(4):349-54.

21. Chung KF, et al. Cough. Chapter 29. In: Mason: Murray and Nadel’s Textbook of Respiratory Medicine. 5th edition, Elsevier: Saunders 2010:p.635.

47. Esposito S, et al. Infez Med 2005;13(2):63-71.

22. Taliercio RM, et al. Cough. Section 12 Pulmonary.

In: Cleveland Clinic: Current Clinical Medicine.

2nd edition, Elsevier: Saunders 2010:p.1032-3.

23. Choby BA. Am Fam Physician 2009;79(5):383-90.

24. American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media. Pediatrics 2004;113(5): 1451-65.

25. Pichichero ME, et al. J Fam Pract 2005;54(4):313-22.

26. Knutson D, et al. Am Fam Physician 2002;65(10):2039-45.

27. Stocks N, et al. Aust Fam Physician 2004;33(5):297-301.

28. Vogel F. Drugs 2002;62(2):309-17.

29. Aggarwal M, et al. Indian J Pediatr 2005;72(3):233-8.

30. Glynne A, et al. J Antimicrob Chemother 1978;4(4):343-8.

31. Rodriguez WJ, et al. Postgrad Med J 1979;55 Suppl 4: 35-8.

48. Dagan R, et al. Pediatr Infect Dis J 1994;13(8):686-90.

49. Maimon N, et al. Eur Respir J 2008;31(5):1068-76.

50. Ahmed A, et al. J Pak Med Assoc 2002;52(1):7-11.

51. Derry JE. Am J Hosp Pharm 1981;38(1):54-8.

52. Drehobl M, et al. Antimicrob Agents Chemother 1997;41(7):1579-83.

53. Kinasewitz G, et al. Eur J Clin Microbiol Infect Dis 1991;10(10):872-7.

54. Mandell LA, et al. Clin Infect Dis 2007;44 Suppl 2:S27-72.

55. Omidvari K, et al. Respir Med 1998;92(8):1032-9.

56. Marlin GE, et al. Thorax 1984;39(11):813-7.

57. Mastro TD, et al. Lancet 1991;337(8734):156-9.

58. Schito GC, et al. J Chemother 1997;9 Suppl 3:18-28.

59. Cazzola M, et al. J Chemother 1991;3(4):245-9.

60. Trigg CJ, et al. Respir Med 1991;85(4):301-8.

In this article, amoxicillin + clavulanate has been abbreviated as Amoxy-Clav.

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clinical study

A Phase IV Clinical Case Study to Evaluate the Efficacy and Safety of a Polyherbal Health Drink (HiOwna-Jr) on Growth, Health and Cognition in Children Dilip V Deshpande*, Padmanabha Rugvedi**

Abstract Background: Malnutrition is an important cause of morbidity in childhood and can be very effectively prevented by appropriate complementary nutritional intervention. Macro- and micronutrients could be fortified as health beverages with essential nutrients, adequate stability and acceptable taste. Aim: To study the clinical safety and efficacy of a polyherbal formulation HiOwna-Jr with regular diet in maintaining health, growth, immunity in respiratory tract infections (RTIs), appetite and cognition in children. Material and methods: This was an open clinical trial conducted in children after getting an approval of the Ethical Committee. Twenty-five children including both male and female, aged between 2-10 years and whose parent or guardian had given the consent to participate in the clinical study were included in the trial. Subsequently, all children underwent a simple physical and systemic examination. All children were advised to consume the investigational product as defined by the protocol as follows: The children in the age group 2-6 years were instructed to take 12.5 g and children in the age group of 7-10 years were instructed to take 25 g of the health drink along with milk orally twice-daily, for a period of two months. All the enrolled children were monitored at monthly intervals for two months, for the effect of health drink as well as any reported or observed adverse effects. At each visit, the subjects were evaluated for general health and growth.

In addition, cognition was evaluated in children aged between 5-10 years. Results: There was a trend towards improvement in the growth as determined by height, weight and body mass index (BMI) including improving immunity as determined by reduction of the frequency of RTI and improving appetite in children aged 2-10 years with HiOwna-Jr. Additionally, cognition parameters like attention, memory and concentration in children aged 5-10 years also showed beneficial results. All the study participants liked the taste with no adverse effects seen. Overall compliance to the study was good. Conclusion: Based on the results of the clinical study, it can be concluded that HiOwna-Jr, when given along with the normal routine diet maintains health, growth, immunity in RTI, appetite and cognition in school-going children.

Keywords: HiOwna-Jr, growth, cognition

H

ealthy eating is an important life skill. It helps children grow, develop and do well in school. Healthy eating prevents childhood and adolescent health problems such as obesity, eating disorders, dental caries and iron deficiency anemia.

It also lowers the risk of future chronic diseases such as heart disease, stroke, diabetes and cancer, and reduces potential healthcare costs (USDA The School Environment, 2000).1

Malnutrition, particularly in early childhood, has both short-term and long-term effects impacting on *Consultant Pediatrician Ashakiran Children Healthcare Centre, RT Nagar, Bangalore **Consultant Ayurveda Physician Vagatma Vaidyashala, Tumkur, Karnataka Address for correspondence Dr Dilip V Deshpande Consultant Pediatrician Ashakiran Children Healthcare Centre #9, 80 Feet Road, HMT Layout, RT Nagar, Bangalore, Karnataka

educability, productivity, morbidity and mortality.2,3 These effects perpetuate poverty and retard national economic development. Mild and moderate forms of malnutrition are not highly visible but affect many people and hence have great public health significance.

Dietary intake and the prevalence of infectious diseases contribute to childrenâ&#x20AC;&#x2122;s nutritional status.

Exclusive breastfeeding is a childâ&#x20AC;&#x2122;s first defence against malnutrition and death.4 Evidence shows that malnutrition, even in its milder forms, can increase the likelihood of mortality from a number of different disease entities and may be associated with upto 56% of all childhood mortality.5,6 This makes malnutrition one of the most important public health problems in developing countries. To have a sustained impact on childhood morbidity and mortality, health programs must include interventions to reduce malnutrition.7

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clinical study

clinical study According to current estimates, about 70% of all childhood mortality in developing countries is due to five major conditions: Diarrheal diseases, acute lower respiratory tract infections (RTIs), malaria, measles and malnutrition.7 Malnutrition is an underlying causes of death for 2.6 million children each year, and it leaves millions more with lifelong physical and mental impairments.

Worldwide, more than 170 million children do not have the opportunity to reach their full potential because of poor nutrition in the earliest months of life.8 Every year, 7.6 million children die before they reach the age of 5, most from preventable or treatable illnesses and almost all in developing countries.9 Malnutrition is an underlying cause of more than a third (35%) of these deaths.10 A malnourished child is upto 10 times as likely to die from an easily preventable or treatable disease as a well-nourished child,10 and a chronically malnourished child is more vulnerable to acute malnutrition during food shortages, economic crises and other emergencies.11 India is home to 40% of the world’s malnourished children and 35% of the developing world’s low-birth weight infants; every year, 2.5 million children die in India, accounting for one in 5 deaths in the world. More than half of these deaths could be prevented if children were well-nourished.12 In spite of its remarkable economic growth in the past decade, India’s progress in reducing child malnutrition has been excessively slow. The prevalence of child malnutrition in India deviates further from the expected level at the country’s per capita income than in any other large developing country.12 A study has highlighted six low-cost nutrition interventions with the greatest potential to save lives of children’s in the first 1,000 days and beyond. Universal coverage of these ‘lifesaving six’ solutions globally could prevent more than two million mother and child deaths each year. The lifesaving six are: Iron folate, breastfeeding, complementary feeding, vitamin A, zinc and hygiene.8 Stunting, or stunted growth, occurs when children do not receive the right type of nutrients, especially in utero or during the first two years of life. Children whose bodies and minds are limited by stunting are at greater risk for disease and death, poor performance in school and a lifetime of poverty.8 Deficiencies of essential micronutrients such as vitamin A and iodine also affect more than half of all preschoolers, and 75% suffer from iron deficiency anemia. These nutritional deficiencies impair growth, physical and

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mental development of children, reduce their resistance to infections and their survival rates, and curtail their future intellectual and reproductive performance and economic productivity. Infection and malnutrition have always been intricately linked. Malnutrition is the primary cause of immunodeficiency worldwide, and we are learning more and more about the pathogenesis of this interaction. Five infectious diseases account for more than one-half of all deaths in children aged <5 years, most of whom are undernourished.

Micronutrient deficiencies have effects such as poor growth, impaired intellect and increased mortality and susceptibility to infection. The worldwide magnitude of parasite infection is enormous. It is understood that parasites may lead to malnutrition, but the extent to which malnutrition causes increased parasite infestation is not known; thus, the conditions need to be addressed together. Nutritional deficiencies associated with pregnancy are associated with poor immune response to infection. Because, this immune deficiency is partially compensated by breastfeeding, this is the single best way to protect infants from infection.12 Breast milk alone does not usually provide all nutrients needed by an infant over six months of age (IDECG 1996). By six months, infants are more likely to be developmentally ready to consume a variety of foods.7 Caretakers are also more likely to accept the feeding of nutritionally adequate semisolid foods to infants of that age. In addition, the infant’s gastrointestinal tract is mature enough to digest such foods and the immune system is developed enough to respond to environmental pathogens. Traditional feeding practices can be improved by modifying the composition, frequency and quantity of food given to infants and young children.7 In populations, where vitamin A deficiency is endemic, a 23-34% reduction in mortality is expected when vitamin A status is improved. Community trials with children 6-71 months of age achieved this impact using universal, periodic supplementation in the form of single megadoses every 3-4 months, small weekly doses or regular use of vitamin A-fortified foods.

Nutritional rickets and osteomalacia are re-emerging in Western societies, particularly in young children and in adolescents of African or Asian descent. Schoolbased studies in the United Kingdom and Finland suggest that a significant proportion of adolescent girls may have subclinical vitamin D deficiency.13,14 The pathophysiology of rickets and osteomalacia in this population may stem from a combination of increased metabolic demands as a result of rapid growth and

puberty, poor vitamin D or calcium intake, high soft drink consumption with increased phosphorous content, decreased physical activity and diminished exposure to sunlight, particularly in individuals with darker skin pigmentation.15 Recent studies suggest a role for vitamin D in innate immunity, including the prevention of RTIs with serum 25-hydroxyvitamin D (25[OH] D) levels being inversely associated with self-reported recent upper RTI (URTI).16 Studies indicate an important public health impact of combined zinc and vitamin A supplementation on URTI in young children, especially in developing countries, where the burden associated with URTI is high, as is the associated morbidity due to otitis media, sinusitis and asthma attacks. Moreover, the effect was sufficiently large to protect the children against the aggravating effect of URTI on growth rates, which are already low as a result of low energy and micronutrient intakes.17 Many nutritional supplements are available in the market for different age groups. HiOwna-Jr is an innovative formula, its ingredients being natural herbs with a high nutrition potential, which provide overall growth and improve cognitive abilities in children.

AIM The aim of the study was to evaluate the clinical efficacy and safety of a polyherbal formulation, HiOwna-Jr Health drink on growth, health and cognition of children.

Material and Methods An open clinical trial was conducted among 25 children at Ashakiran Children Healthcare Centre, HMT Layout, RT Nagar, Bangalore. Local Ethical Committee approval was obtained before initiation of the study.

Subject Selection Criteria Inclusion Criteria Both male and female children aged between 2-10 years and whose parent or guardian had given the consent to participate in the clinical study were included for the present study.

Exclusion Criteria Children with cardiac, hepatic or renal failure, and those children who are regularly on any treatment or concurrently taking medicines for any illness were excluded from the study. Children with congenital anomalies like cleft lip, etc., which hampers food

intake and children with a strong history of food or drug allergy of any kind were also excluded. If the parent or guardian is not willing to provide informed consent or abide by the requirements of the study, then children were not included in the study.

Informed Consent Process All parents who were willing for their children to participate in the study were given detailed description about the investigational product, nature and duration of the study using a patient information sheet, in a language that was nontechnical and easily understood by the study subject’s parent or guardian. The parents were given adequate time to read it before the informed consent is signed. Also, their responsibilities after entering the study were explained. Subjects were prescreened by the investigators for the criteria indicated in the subject selection section. Only those subjects whose parents/guardians were willing to follow instructions and had an updated medical history on file with the investigator were entered in the study.

A written informed consent by the parent or guardian was obtained from each study subject using an ‘informed consent form’. The investigator retained the original copy of the signed informed consent and the subject received a copy of the signed informed consent.

Study Procedure The demographic details of the subjects are given in Table 1. The clinical assessment was made on careful history, signs and symptoms and physical check-up.

All children were instructed to consume the health drink as defined by the protocol as follows: All the children at the age group 2-10 years were instructed to take HiOwna-Jr at a dose of 12.5 g and children in the age group of 7-10 years were instructed to take 25 g of HiOwna-Jr orally twice-daily with milk for the period of eight weeks.

Children were assessed at entry, Week 4 and Week 8.

At each visit, the subjects were evaluated for general health, frequency of RTIs, appetite and growth. In addition, cognition was evaluated in children aged Table 1. Demographic Details of the Clinical Trial (n = 25) Gender (Male:Female) Age (Mean ± SD in years)

12:13 5.13 ± 2.92

Height (cm)

102.9 ± 19.75

Weight (kg)

15.64 ± 6.44

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clinical study

clinical study between 5-10 years. Cognition was evaluated taking into consideration attention, memory and concentration.

Ten objects commonly seen by the children were kept in an order and the children were asked to observe the objects and recollect and tell the name of the object without seeing them. This test was done differently for the different ages ranging from 5 to 10 years.

Accordingly scored from 0 to 3, where: ÂÂ

0: Not able to recollect even a single object

ÂÂ

1: Able to recollect 1-3 of the object

ÂÂ

2: Able to recollect 4-7 objects

ÂÂ

3: Able to recollect >7 of the objects.

At each follow-up visit, the investigator recorded any information about intercurrent illness, therapeutic interventions and concomitant medication/s. All the adverse events reported or observed by patients were recorded with information about severity, date of onset, duration and action taken regarding the study drug.

Follow-up and Assessment Subjects were assessed at entry, Week 4 and Week 8.

At each visit, the subjects were evaluated for general health, frequency of RTIs, appetite and growth. In addition, cognition was evaluated in children aged between 5-10 years.

Adverse Event Assessment At each follow-up visit, all the adverse events reported or observed by patients were recorded with regard to severity, date of onset, duration and action taken regarding the study drug.

The adverse events were predefined as ‘Unrelated’ (a reaction that does not follow a reasonable temporal sequence from the administration of the drug), ‘Possible’ (follows a known response pattern to the suspected drug, but could have been produced by the subject’s clinical state or other modes of therapy administered to the subject) and ‘Probable’ (follows a known response pattern to the suspected drug that could not be reasonably explained by the known characteristics of the subject’s clinical state).

Primary and Secondary Endpoints The predefined primary endpoints were improvement in symptoms of maintaining health, growth, RTI, appetite and cognition in children. The predefined secondary endpoints for short-term safety were assessed by incidence of adverse events during the study period, and overall compliance to the drug treatment.

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Statistical Analysis All values are expressed as compared to ‘At entry’ as mean ± SD. The statistical analysis was performed using repeated measures of ANOVA followed by Bonferroni’s multiple comparison test for height, weight and body mass index (BMI). Parameters such as loss of appetite, frequency of RTI, frequency of other infections, cognition, concentration and memory was analyzed by repeated measures of ANOVA followed by Dunnett’s multiple comparison test. The minimum level of significance was fixed at p < 0.05. Statistical analysis was performed using GraphPad Software (Version 4.03), San Diego, California, USA

Table 2. Effect of HiOwna-Jr on Clinical Parameters of the Study Parameter Height (cm)

Treatment duration Initial

1st month

2nd month

102.9 ± 19.75

103.0 ± 19.71

103.8 ± 19.75 a,bp

Weight (kg)

15.64 ± 6.44

15.72 ± 6.39

BMI

15.08 ± 0.93

15.22 ± 0.82

Appetite

1.40 ± 1.04

1.96 ± 0.89

Mean BMI among children was initially 15.08 ± 0.93 (kg/m2), which improved to 15.22 ± 0.82 at the end of 1st month, showing further improvement to 15.36 ± 0.91 by the end of study with a significance value of p < 0.001. The effect of HiOwna-Jr on appetite of the subjects was also significant with p < 0.05 with mean scores of 1.40 ± 1.04 initially, which improved to 1.96 ± 0.89 by the end of 1st month.

This was further improved to 2.16 ± 0.94 by the end of 2nd month indicating a significant response in the subjects.

The effect of HiOwna-Jr in improving the immunity in children was studied with respect to the frequency of respiratory and other infections, which affect the children recurrently. The statistical analysis shows significant results in reduction of infections. The initial score of 1.96 ± 1.02 for respiratory infections was reduced to 0.60 ± 0.71, at the end of 1st month. This was further reduced to 0.16 ± 0.37 with high significance of p < 0.001 on both the intervals as compared to the initial value. Similarly, for other infections, the initial score of 2.00 ± 0.82 was reduced to 1.36 ± 0.76 at the end of 1st month with significance of p < 0.05.

< 0.001

2.16 ± 0.94 ap

Frequency of RTIs

1.96 ± 1.02

Frequency of other infections

2.00 ± 0.82

< 0.001

15.36 ± 0.91 ap

RESULTS The demographic details are provided in Table 1.

Statistical studies performed to measure the effect of HiOwna-Jr are shown in Table 2. The effect of HiOwna-Jr on height of children shows significant improvement. Initially, the mean height was 102.9 ± 19.75, which improved to 103.0 ± 19.71 at the end of 1st month and further improved to 103.8 ± 19.75 cm at the end of 2nd month with a significance of p < 0.001 compared to initial height. The mean weight (kg) initially was 15.64 ± 6.44, which improved to 15.72 ± 6.39 at the end of 1st month, and further improved to 16.14 ± 6.42 with p < 0.001; significance as compared to both the previous values.

16.14 ± 6.42 a,bp

(kg/m2)

< 0.001

< 0.05

0.60 ± 0.71

0.16 ± 0.37

ap

ap

< 0.001

1.36 ± 0.76 ap

< 0.05

< 0.001

0.48 ± 0.65 ap

< 0.001; bp < 0.01

Cognition

2.08 ± 0.81

2.36 ± 0.49

2.36 ± 0.49

Concentration

2.28 ± 0.61

2.36 ± 0.49

2.36 ± 0.49

Memory

2.12 ± 0.78

2.36 ± 0.49

2.56 ± 0.51

Note: is Significance as compared to at Initial values and is Significance as compared to 1st month values. a

b

The score by the end of the study was 0.48 ± 0.65, which has a significance value of p < 0.001 as compared to initial value and p < 0.01 as compared to the value at the end of 1st month.

The effect of HiOwna-Jr on mental attributes like cognitive abilities, concentration and memory was found to be encouraging. For cognition of children the initial value was 2.08 ± 0.81, which improved to 2.36 ± 0.49 at the end of 1st month and also by the end of study. The score of concentration in children was 2.28 ± 0.61 initially and improved to 2.36 ± 0.49 at the end of 1st month and also at the end of 2nd month.

The memory score was initially 2.12 ± 0.78, which improved to 2.36 ± 0.49 by the end of 1st month and further improved to 2.56 ± 0.51 by the end of the study.

The overall impression by the investigator indicated that seven children showed good response (28%) and 18 showed excellent response (72%) to treatment.

All children completed the trial and no adverse drug reaction was reported in the trial.

DISCUSSION Much of a child’s future is determined by the quality of nutrition in the early infancy. This is a critical window when a child’s brain and body are developing rapidly and good nutrition is essential to lay the foundation for a healthy and productive future. If children do not get

the right nutrients during this period, the damage is often irreversible.8 For complementary foods to be appropriate in energy and nutritional value, most staple foods (wheat, millet, corn, rice, cassava) need to be enriched. Ingredients with high nutrient-to-energy and energy-to-volume values can often be found in local environments. Reducing the water content and introducing animal foods, fats, oilseeds, nuts, legumes and varied fruits and vegetables to the staple diet can improve nutritional density.18 HiOwna-Jr contains principal herbal ingredients like Nartaka (Eleusine coracana), Maricha (Piper nigrum), Amalaki (Emblica officinalis), Mandukaparni (Centella asiatica) and other nutrients like sucrose, peeyusha (colostrum) skimmed milk powder, corn solids (maltodextrin), pea protein powder, whey protein concentrate, minerals (calcium, phosphorous, iron, magnesium, zinc, chromium, selenium, molybdenum, iodine), vitamins (A, C, D, E, K, B1, B2, B6, B12, niacin, biotin, folic acid and pantothenic acid). These ingredients provide balanced nutrition and help in promoting overall health of children by their nutritive, energy boosting, digestive, memory enhancing and immunomodulatory properties. Proteins, carbohydrates and fats provide energy, promote growth and development and regulate body functions. Vitamins and minerals have a beneficial effect on linear growth,

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clinical study health and cognitive development in school children.

The beneficial effects of the health drink are discussed as follows:

Nutritive and Health-promoting E. coracana is known for its nutritive and strengthenhancing properties.19,20 It is rich in protein, iron, calcium, phosphorus, fiber and vitamin content. The calcium content is higher than all cereals. Ragi has the best quality protein along with the presence of essential amino acids, vitamin A, vitamin B and phosphorus.

Thus, it is a good source of diet for growing children.

Ragi provides highest level of calcium, antioxidants, phytochemicals, which makes it easily and slowly digestible. Malting of finger millet improves its digestibility, sensory and nutritional quality as well as pronounced effect in the lowering the antinutrients.21 Bovine colostrum has been regarded as an excellent source of nutrition, which helps in promoting body growth.22 Proteins, carbohydrates and fat are required for growth, maintenance and highly specialized functions of the body. These macronutrients are also used as the energy source.23 Vitamins and minerals are known for their health promoting functions in the body.24

Enhancement of Nutrient Absorption and Gastroprotective Effects P. nigrum, which is a rich source of piperine increased the secretion of bile in experimental studies.25 This suggests that P. nigrum aids the digestion and absorption of dietary fats.

P. nigrum was found to offer protection against the gastric damage caused by gastric irritant agents, which might be related to the inhibition of gastric motor activity and the stimulation of prostaglandin synthesis.26 This is indicative of the gastroprotective activity that P. nigrum exerts.

Dietary piperine, by favorably stimulating the digestive enzymes of pancreas, enhanced the digestive capacity and significantly reduced the gastrointestinal food transit time, enhanced the bioavailability of a number of phytochemicals by inhibitory influence on enzymatic drug biotransforming reactions in the liver.

Piperine’s bioavailability-enhancing property is also partly attributed to increased absorption as a result of its effect on the ultrastructure of intestinal brush border.27

Immunomodulatory Activity An experimental study showed that the presence of Amla (E. officinalis) was effective against the cytotoxic effects

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of chromium-induced oxidative damage of murine macrophages and resulted in an enhanced cell survival, decreased free radical production and higher antioxidant levels similar to that of control cells. Further, chromium (VI) treatment resulted in decreased phagocytosis and γ-interferon (γ-IFN) production while Amla (E. officinalis) inhibited chromium-induced immunosuppression and restored both phagocytosis and γ-IFN production by macrophages significantly.28 These findings suggest the cytoprotective and immunomodulatory potential of E. officinalis fruit. In another in vitro study, Amla (E. officinalis) relieved the immunosuppressive effects of chromium on lymphocyte proliferation and even restored the interleukin-2 (IL-2) and γ-IFN production considerably.29 An experimental study conducted on mice demonstrated that the aqueous extract of E. officinalis was very effective in reducing cyclophoshpamide-induced suppression of humoral immunity.30 All the above studies indicate the immunomodulatory potential of E. officinalis. In a clinical study, it was proved that Bovine colostrum had the ability to increase IgA, which indicated that it had the potential to enhance human special immune response.31

Promoting Mental Health The results of a double-blind clinical trial on C. asiatica indicated that there was a significant increase in the general mental ability of mentally retarded children after three months and six months of drug administration.

Significant improvement was found in the overall general adjustment, attention and concentration after six months.32 In an experimental study, it was concluded that C. asiatica leaf extract had a neuronal dendritic growth stimulating property; hence, the extract could be used for enhancing neuronal dendrites in stress and neurodegenerative and memory disorders.33 These studies, indicate that C. asiatica improves memory and learning ability. Multiple micronutrients such as vitamins and minerals when delivered through either supplements or fortified foods were found to have a positive effect on reasoning ability and academic performance in school children.34

of RTI and improving appetite in children aged 2-10 years. The improvement in the growth corresponded to the normal natural growth in the children, which implies that HiOwna-Jr helps in the natural normal linear growth of children. Cognition parameters like attention, memory and concentration evaluated in school-going children aged 5-10 years also showed beneficial results. All the children liked the taste and flavor. Overall compliance to the study was good. Therefore, it can be concluded that HiOwna-Jr helps to maintain adequate natural linear growth, enhances immunity against recurrent RTI and better academic performance in school children by improving cognition.

REFERENCES 1. Mixon HH. Nutrition in the Middle Grades: Adolescent Food Habits and Marketing Strategies That Work. National Food Service Management Institute, The University of Mississippi. October, 2001.

2. World Health Organization. Nutrition for health and development. WHO: Geneva, 2000. URL: http://www. searo.who.int/en/Section13/Section38.htm.

3. Administrative Committee on Coordination/Standing Committee on Nutrition. 4th Report on the world nutrition situation. ACC/SCN in collaboration with IFPRI: Geneva; 2000.

4. World Health Organization. HIV transmission through breastfeeding: a review of available evidence. UNICEF: New York; 2004. URL: http://www.who.int/reproductivehealth/docs/hiv_ infantfeeding/breastfeeding.html.

5. Pelletier DL, et al. Am J Public Health 1993;83(8):1130-3.

6. Pelletier DL, et al. Bull World Health Organ 1995;73(4): 443-8.

11. Abdallah, Saade, Gilbert Burnham (Eds.). Public Health Guide for Emergencies. The Johns Hopkins School of Hygiene and Public Health and The International Federation of Red Cross and Red Crescent Societies: Boston 2000:p.453.

12. Schnadower D, et al. Pediatrics 2006;118(5):2226-30.

13. Lehtonen-Veromaa M, et al. Eur J Clin Nutr 1999;53(9): 746-51.

14. Das G, et al. Arch Dis Child 2006;91(7):569-72.

15. Moncrieff MW, et al. Arch Dis Child 1973;48(3):221-4.

16. Ginde AA, et al. Arch Intern Med 2009;169(4):384-90.

17. Kartasurya MI, et al. Br J Nutr 2012 Mar 14:1-10.

18. Brown KH, Allen L, Dewey K. 1995. Complementary feeding: A state-of-the-art review. Paper prepared for UNICEF/WHO consultation, 28-30 November 1995, Montpelier, France.

19. Golokavasi Lala Shaligramji Vaishya. Brihannighanturatnakara. Khemraj Shrikrishnadas Prakashan, Mumbai, 7-8 Vol, p. 639.

20. Sastri BN. The Wealth of India CSIR. Vol III, New Delhi.

1952:p.165.

21. Desai AD, et al. Adv J Food Sci Technol 2010;2(1):67-71.

22. Kaviraj Ambikadattashastri. Sushruta Samhita. Part I. 11th edition, Chaukambha Sanskrit Sansthan, Varanasi, 1997:p.176.

23. Joshi SA. Nutrition and Dietetics. Tata McGraw-Hill Publishing Company Limited. 1992:p.46-69.

24. Best C, et al. Nutr Rev 2011;69(4):186-204.

25. Ganesh Bhat B, et al. Nahrung 1987;31(9):913-6.

26. Al-Moflehi A, et al. Pharmacogny Mag 2005;1(2):64-8.

27. Srinivasan K. Crit Rev Food Sci Nutr 2007;47(8):735-48.

28. Sai Ram M, et al. Phytother Res 2003;17(4):430-3.

29. Sai Ram M, et al. J Ethnopharmacol 2002;81(1):5-10.

7. Katona P, et al. Clin Infect Dis 2008;46(10):1582-8.

30. Haque R, et al. Hum Exp Toxicol 2001;20(12):643-50.

8. Nutrition in the First 1,000 Days, State of the World’s Mothers 2012. Save the Children International, USAID; 4-16.

31. He F, et al. FEMS Immunol Med Microbiol 2001;31(2): 93-6.

32. Appa Rao VR, et al. Indian J Psychiat 1977;19(4):54-9.

9. UNICEF. The State of the World’s Children, 2012. Table 2. p.95.

33. Mohandas Rao KG, et al. Evid Based Complement Alternat Med 2006;3(3):349-57.

10. Black RE, et al. Lancet 2008;371(9608):243-60.

34. Eilander A, et al. Am J Clin Nutr 2010;91(1):115-30.

CONCLUSION This clinical study clearly demonstrates that HiOwna-Jr, a polyherbal natural health drink supplement, along with regular diet showed a trend towards improvement in the growth as determined by height, weight and BMI including improved immunity as determined by reduction of the frequency

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clinical study

S GUNASEKARAN*, TS RENUGA DEVI**, A RAMANAND†, M MADURAI VEERAN†

Abstract Anemia has been recognized as public health problem for many years. There has been little progress and the global prevalence of anemia remains unacceptably high. Anemia is an indicator or both poor nutrition and poor health. It is a condition wherein there is a deficiency of red blood cells, or hemoglobin. This leads to a lack of oxygen-carrying ability of the body. Increasing the hemoglobin concentration or red blood cells is a major target in treatment of anemia. Hemoglobin level may be increased by the use of hemoglobin increasing agents, such as Erypro. Ten patients of the same age and blood group from AKN Nursing Home, Kilpauk, Chennai were enrolled in the present investigation and they were allowed to take prescribed drug (Erypro) thrice weekly for a period of six months. Before the drug therapy, the Fourier transform infrared spectroscopy (FTIR) blood spectra were recorded (pre-treatment). The FTIR spectra were recorded at 3rd and 6th months (post-treatment) after treatment was initiated. Some remarkable differences were seen in terms of spectral profiles. Erypro drug therapy reduced some specific wave numbers: 1,035 cm-1 by 27.3%, 1,230 cm-1 by 27.5%, 1,400 cm-1 by 30.3% and 1,542 cm-1 by 13.6%. These data suggest that Erypro drug can be used to increase the hemoglobin level of anemic patient.

Keywords: Anemia, Erypro, FTIR spectroscopy, efficacy, blood serum

A

nemia is a global public health problem affecting both developing and developed countries with major consequences for human health as well as social and economic development. It occurs at all stages of the life cycle, but is more prevalent in pregnant women and young children. In 2002, iron deficiency anemia (IDA) was considered to be among the most important contributing factors to the global burden of disease.1 Anemia is defined as a decrease in hemoglobin level to below 130 g/l (13 g/dl) in men and below 120 g/l (12 g/dl) in women. Hemoglobin is the pigment in the red corpuscles, which enables them to transport oxygen from the lungs to body tissues. Anemia therefore causes a deficiency in the amount of oxygen carried to the tissues. Consequently, its main symptoms are pallor of the skin and mucous membranes, fatigue, palpitations, soft systolic murmurs, shortness of breath, headaches and dizziness, which can lead to coma.

The symptom level is closely related to the degree of anemia, how fast it sets in, and the terrain at onset.

Chronic renal insufficiency is a pathophysiological process, which can have many causes and leads to a reduction in the number and function of nephrons *Spectrophysics Research Laboratory, Pachaiyappa’s College, Chennai **Postgraduate, Dept. of Physics, Women’s Christian College, Chennai †Postgraduate, Research Dept. of Physics, Loyola College, Chennai

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(functional structures of the kidney). It is a long and often insidious process, with the patient remaining asymptomatic until 75% of the nephrons are lost.2 Anemia is frequent in patient with cancer and often multifactorial, connected with the cancer itself or with its treatment. Chemotherapy given in cancer treatment is not specific. It destroys both normally dividing cells and cancer cells, those of the digestive tract and bone marrow in particular. Inhibition of erythropoiesis will lead to anemia.

There have been few reports on the efficacy and safety of the some drugs.3-9 Though investigations on the efficacy and the safety of these drugs have been done by many, not much work is done on the efficacy of these drugs spectroscopically.

Aim To employ Fourier transform infrared spectroscopy (FTIR) to analyze the efficacy of the erypro drug therapy.

Material and Methods Ten patients of the same age and blood group from AKN Nursing Home, Kilpauk, Chennai were enrolled in the present investigation. They were instructed to take

the prescribed drug (Erypro) thrice weekly for a period of six months. Two milliliter of blood samples were collected by vein puncture from healthy volunteers and anemic patients. After treatment, blood samples were once again collected from those patients who underwent treatment. After centrifugation of blood in refrigerated centrifuge, the plasma aliquots were transported to the laboratory in a portable freezer and kept at 20°C until analyzed. It has been reported that infrared absorption spectrum of the thiocyanate ion (SCN) includes absorption at 2,060 cm-1 in a spectral region, where serum samples and subsequently normalizing all of the spectra of equal intensities therefore compensated for the imprecision in the film preparation.

One drop of each sample was spread evenly over the surface of a thallium bromide cell. All specimens were air-dried to form a uniform thin film on the thallium bromide cell for three minutes prior to measuring the infrared spectra to eliminate the absorption band of water. The FTIR spectra of the serum samples were recorded over the region 450-4,000 cm-1 with resolution of 1 cm-1 using Perkin-Elmer spectrum-one FTIR spectrometer at IIT, Chennai, India. Before the drug therapy, the FTIR blood spectra were recorded (pre-treatment). To find the efficacy of the above said drug in patients, the FTIR spectra were recorded at 3rd and 6th months after treatment. The spectra were baseline corrected and they were normalized to acquire identical area under the curves and the maximum absorbance values of the corresponding characteristics band were noted.

RESULTS AND DISCUSSION Before erythropoietin (EPO) came on the market, severe anemias were treated mainly by blood transfusion with all the associated constraints and risks (transmission of viral infections such as acquired-immunodeficiency syndrome [AIDS], or hepatitis B and C, immune problems). Patients with chronic renal insufficiency (CRI) under dialysis received iron and folic acid and were systematically and regularly transfused to maintain their hemoglobin levels. Anabolic steroids were also used, with limited success and many complications.

In cancer cases, anemia was corrected by transfusion when the hemoglobin level fell below 8 g/dl. The development of recombinant EPO, produced using the techniques of genetic engineering, has therefore revolutionized the treatment of anemias since, the first EPO was put on the market in 1988. There are three types of EPO: Epoetin α, epoetin β and darbepoetin α.

EPO is a proteinaceous hormone, which in its recombinant form (r-Hu-EPO) is produced industrially by a cell line

from mammal cells into which the EPO gene has been inserted). Erypro is a synthetic version of the naturallyoccurring hormone EPO. EPO is produced by healthy kidneys. It stimulates the bone marrow to produce red blood cells, which carry oxygen around the body. Eprex or Erypro was the first r-Hu-EPO put on the market by Johnson and Johnson in Europe. It is the product name of epoetin a and is used to treat anemia, in patients with chronic kidney failure.10 It is also used for treating anemia in adults who are receiving chemotherapy to treat solid tumors, malignant lymphoma or bone cancer.

The infrared spectrum is an essence of reflection of the infrared color pattern characteristic of the sample. The basis of quantization is that each constituent contributes a unique absorption pattern to the overall spectrum governed by the unique set of molecular vibrational characteristic of each distinct molecular species. The quantitative information is carried by the relative intensities of vibrational frequencies of the various constituents contributing to the unique absorption profile of each serum specimen.

The infrared spectrum of serum includes spectral contributions from protein, cholesterol, triglycerides, urea, glucose and other more dilute contributes a complex set of several absorptions falling within the mid-infrared spectral region.11,12 It is impossible to find any single absorption band that can serve as the basis to quantify any single component; coincident absorptions from other species would degrade or completely sabotage the effort. A vibrational band assignment of the absorption bands of the spectra is done with the idea of the group frequency of various constituents of the serum samples.

A satisfactory assignment of the vibrational band has been carried out by interpreting the well-established

1.6 1.4 1.2 Absorbance

Efficacy of Erypro on Anemic Patients: A Spectroscopic Approach

Healthy Anemia Post 1 Post 2

1.0 0.8 0.6 0.4 0.2 0.0

–0.2 500 1000 1500 2000 2500 3000 3500 4000 Wave number (cm–1)

Figure 1. FTIR overlaid spectra of anemic patient.

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clinical study Table 1. Absorbance of Specific Modes of Vibration: To Find the Efficacy of Erypro in Anemic Patients Sample 1

2

3

4

5

6

7

8

9

10

326

Wavelength (cm-1)

Status

infrared spectra of blood and serum.13 Figure 1 presents the FTIR overlaid spectra of an anemic patient to find the efficacy of erypro.

Pre

0.3145

0.6545

0.6174

1.0327

Post 1

0.2716

0.5739

0.5396

0.9634

Post 2

0.2267

0.4985

0.43.13

0.8924

% of Eff

–27.91

–27.91

–30.14

–13.58

Pre

0.3654

0.6475

0.6349

1.0252

In order to find the efficacy of Erypro, the absorption values of the vibrational bands at 1,035, 1,230, 1,400 and 1,542 cm-1. The absorption peaks at 1,035 cm-1 is due to the C-O stretch of the b-anomer. The vibrational band at 1,230 cm-1 is due to lipid phosphate band arising from the asymmetric PO2 stretching. The peak at 1,400 cm-1 may also be considered due to COO– stretch of ionized amino acid chains. The strong absorption band present at 1,542 cm-1 is due to the amide-II (or) N-H bending vibrations that are strongly coupled of the C-N stretching vibrations of the protein amide groups.

These vibrational bands of both pre- and post-treatment spectra were noted and the percentage of efficacy were calculated using the formula (pre-post)/pre*100 and are tabulated in Table 1.

Post 1

0.3243

0.5617

0.5442

0.9569

CONCULSION

Post 2

0.2858

0.4812

0.4424

0.8871

% of Eff

-27.49

-27.49

-30.31

-13.37

Pre

0.3978

0.6982

0.7850

1.0580

Post 1

0.3428

0.6025

0.6635

0.9827

Post 2

0.2897

0.5065

0.5452

0.9022

% of Eff

–27.17

–27.44

–30.54

–13.78

Pre

0.3215

0.5923

0.8237

1.0322

Post 1

0.2787

0.5176

0.6213

1.0248

Post 2

0.2335

0.4332

0.5696

0.8919

% of Eff

–27.37

–27.37

–30.84

–13.59

Pre

0.4080

0.7265

0.7402

1.0221

Post 1

0.3529

0.6231

0.6359

0.9537

Post 2

0.2941

0.5541

0.5176

0.8832

% of Eff

–27.92

–27.92

–30.07

–13.58

1,035

1,230

1,400

1,542

Pre

0.2582

0.5912

0.6361

1.0363

Post 1

0.2345

0.5260

0.5894

0.9541

Post 2

0.1882

0.4283

0.4423

0.8973

% of Eff

–27.11

–27.55

–30.46

–13.41

Pre

0.2714

0.6524

0.7802

1.0984

Post 1

0.2374

0.5942

0.6642

1.0275

Post 2

0.1972

0.4728

0.5424

0.9486

% of Eff

–27.33

–27.52

–30.48

–13.63

Pre

0.3087

0.5942

0.8044

1.0572

Post 1

0.2665

0.5214

0.6581

0.9869

Post 2

0.2246

0.4308

0.5621

0.9135

% of Eff

–27.24

–27.49

–30.12

–13.59

Pre

0.3916

0.6110

0.6871

1.0241

Post 1

0.3379

0.5388

0.5977

0.9541

Post 2

0.2847

0.4657

0.4809

0.8823

% of Eff

–27.30

–27.30

–30.01

–13.85

Pre

0.3075

0.6996

0.7952

1.0914

Post 1

0.2666

0.6129

0.6756

1.0226

Post 2

0.2238

0.5059

0.5517

0.9437

% of Eff

–27.21

–27.68

–30.62

–13.53

Indian Journal of Clinical Practice, Vol. 23, No. 6, November 2012

It has been well-demonstrated that the study of FTIR spectra of dried serum films may be used to differentiate the healthy and diseased subjects. Some remarkable differences are elucidated in terms of spectral profiles and absorption bands. It is striking that after six months of drug therapy, the absorption peak values of the patients blood spectrum, almost resembled the healthy volunteers spectra. The final values at the end of the treatment reach closer to the normal level and may have implications for diagnosis based on FTIR spectroscopy.

density lipoprotein cholesterol, apolipoproteins, and lipid ratios in patients with hypercholesterolemia: additional results from the STELLAR trial. Clin Ther 2004;26(9): 1388-99.

4. Ridker PM, Morrow DA, Rose LM, Rifai N, Cannon CP, Braunwald E. Relative efficacy of atorvastatin 80 mg and pravastatin 40 mg in achieving the dual goals of low-density lipoprotein cholesterol <70 mg/dl and C-reactive protein <2 mg/l: an analysis of the PROVEIT TIMI-22 trial. J Am Coll Cardiol 2005;45(10): 1644-8.

5. Hunninghake D, Bakker-Arkema RG, Wigand JP, Drehobl M, Schrott H, Early JL, et al. Treating to meet NCEP-recommended LDL cholesterol concentrations with atorvastatin, fluvastatin, lovastatin, or simvastatin in patients with risk factors for coronary heart disease.

J Fam Pract 1998;47(5):349-56.

6. Pedersen TR, Tobert JA. Benefits and risks of HMG-CoA reductase inhibitors in the prevention of coronary heart disease: a reappraisal. Drug Saf 1996;14(1):11-24.

7. Ganz DA, Kuntz KM, Jacobson GA, Avorn J. Costeffectiveness of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor therapy in older patients with

myocardial infarction. Ann Intern Med 2000;132(10): 780-7.

8. Guérin M, Bruckert E, Dolphin PJ, Turpin G, Chapman MJ. Fenofibrate reduces plasma cholesteryl ester transfer from HDL to VLDL and normalizes the atherogenic, dense LDL profile in combined hyperlipidemia. Arterioscler Thromb Vasc Biol 1996;16(6):763-72.

9. Eisenberg S. Role of fibric acids in the management of hyperlipidemia. Curr Opin Lipidol 1990;1(1):34-8.

10. Dunn CJ, Wagstaff AJ. Epoetin alfa. A review of its clinical efficacy in the management of anaemia associated with renal failure and chronic disease and its use in surgical patients. Drugs Aging 1995;7(2):131-56.

11. Liu KZ, Dembinski TC, Mantsch HH. Rapid determination of fetal lung maturity from infrared spectra of amniotic fluid. Am J Obstet Gynecol 1998;178(2):234-41.

12. Hall JW, Pollard A. Near-infrared spectrophotometry: a new dimension in clinical chemistry. Clin Chem 1992;38(9):1623-31.

13. Heise HM, Marbach R, Koschinsky T, Gries FA. Multicomponent assay for blood substrates in human plasma by mid-infrared spectroscopy and its evaluation for clinical analysis. Appl Spectrosc 1994;48(1):85-95.

The efficacy of Erypro on anemic patients is highly favorable and it has been proved systematically using FTIR spectroscopy in the present study. Erypro therapy reduced some specific wave numbers are 1,035 cm-1 by 27.3%, 1,230 cm-1 by 27.5%, 1,400 cm-1 by 30.3% and 1,542 cm-1 by 13.6%. These data suggest that Erypro drug is used to increase the hemoglobin level of anemic patient.

REFERENCES 1. World Health Organization. World Health Report 2002 Reducing Risks, Promoting Healthy Life. Geneva.

2. Koury MJ, Bondurant MC. The mechanism of erythropoietin action. Am J Kidney Dis 1991;18(Suppl 1): 20-3.

3. Jones PH, Hunninghake DB, Ferdinand KC, Stein EA, Gold A, Caplan RJ, et al. Effects of rosuvastatin versus atorvastatin, simvastatin, and pravastatin on non-high-

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original study

Bacteriological Spectrum of Surface Wound Infections and their Antimicrobial Susceptibility Pattern in a Rural Medical College Hospital in West Bengal Munmun Das*, Hirak Jyoti Raj**

Abstract Aims: To study the bacterial etiology of surface wound infections and their antimicrobial susceptibility pattern.

Material and methods: A total of 500 consecutive clinical samples from different surface wounds were collected and processed in the Microbiology Laboratory from January to December 2006. Results: There were a total of 351 bacterial isolates from 334 culture-positive samples, which consisted of 151 gram-negative bacilli and 200 gram-positive cocci. Staphylococcus aureus was the commonest isolate (48.3%) followed by Escherichia coli (16.5%) and Pseudomonas spp. (8.55%) and coagulase-negative Staphylococcus (8.55%). Methicillin resistance in S. aureus was found to be 35.9% and all gram-positive isolates showed 100% sensitivity to vancomycin. For gram-negative bacilli, amikacin was most effective drug, while ciprofloxacin showed least sensitivity. Piperacillin emerged as most sensitive agent against Pseudomonas spp. Conclusions: The antimicrobial susceptibility pattern suggests that drug therapy for wound infections should always be guided by the sensitivity reports for effective management of surface wound infections.

Keywords: Surface wounds, MRSA, antibiotic resistance

I

nfection is a common problem in surface wounds, which occur as a complication of surgery, trauma and secondary to invasive procedures. It is one of the key reasons why wound healing may stall, leading to increased risks of patient morbidity and mortality.

Bacteria seek to establish themselves in ecological niches to ensure their own survival and evolution.

An open wound provides a suitable niche. The longer a wound is open, the more inviting it is for bacteria.1

Source of wound infections can include patientsâ&#x20AC;&#x2122; own commensal flora or organisms present in the hospital environment, which are introduced to the patient by medical procedures or following surgery or trauma.2 Distribution pattern of microorganisms is always

*Assistant Professor **Postgraduate Student Dept. of Microbiology, Burdwan Medical College, Burdwan, West Bengal Address for correspondence Dr Hirak Jyoti Raj C/O: Chitta Mukherjee Kantapukur-Laxmipur Math, Burdwan - 713 101, West Bengal E-mail: hirak17raj@gmail.com

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Indian Journal of Clinical Practice, Vol. 23, No. 6, November 2012

subject to a combination of chemical, physical and biological factors and every microbial species has specific demands, which must be satisfied for its continuous survival in any given place. Surface wounds do not always provide identical conditions and therefore different wounds support different types of microorganisms.3 In order of frequency, Staphylococcus aureus accounts for 30-50% of skin and soft tissue infections followed by gram-negative bacteria, nonfermenters, Streptococcus pyogenes and anaerobes.4 Resistance to antimicrobial drugs is increasing at an alarming rate among both gram-positive and gram-negative bacteria. Clinically important bacteria have developed not only single but multiple drug resistance - the legacy of past decades of antimicrobial uses and misuse. Development of resistance in S. aureus to antimicrobial agents is a major problem, starting with resistance to penicillin G due to b-lactmase production followed by development of methicillin-resistant S. aureus (MRSA) in the 1960s by the mecA gene.5 Continuous surveillance is therefore necessary to monitor antimicrobial resistance and to guide antibacterial therapy.

Original Study

Original Study Aim To find out bacteriological spectrum of surface wound infection and their antimicrobial susceptibility pattern in a tertiary care hospital to guide rational antimicrobial therapy.

Material and Methods This prospective study included consecutive 500 pus/wound swab samples obtained from different types of wounds of the patients attending Burdwan Medical College and Hospital during the year 2010.

Two samples were obtained from each patient before administration of an antibiotic or antiseptic dressing.

One sample was subjected to direct Gram-staining examination by preparation of smear for presumptive identification of likely organism/s present. The second sample was utilized for culture and sensitivity testing.

While collecting pus from abscesses, wounds or other sites, special care was taken to avoid contamination from commensal organisms of skin. Each sample was inoculated on sheep blood agar and MacConky agar plates at 37oC for 18-24 hours. Suspected colonies were identified on the basis of morphological characteristics

by Gram-stain and by conventional biochemical methods according to standard microbiological techniques.6 All the identified bacteriological pathogens were subjected to antimicrobial susceptibility testing by the standard disc diffusion method recommended

by National Committee for Clinical Laboratory Standards (NCCLS).7 Standard strains of Escherichia coli ATCC 25922, S. aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 27853 were used as reference strains for the standardization of antibiotic susceptibility testing.

Detection of methicillin resistance was carried out by standard screening procedure using 10 µg oxacillin disc obtained from HiMedia Laboratory.7 Methicillin resistance for S. aureus was considered present when a zone of inhibition was ≤10 mm, and for coagulasenegative Staphylococcus when the same was found to be ≤17 mm.

Results Out of 500 surface wound samples processed in this study, 334 (66.8%) were culture-positive and 166 (33.2%) samples yielded no growth on aerobic culture.

Nine samples showed growth of diphtheroids and aerobic spore-bearing bacilli and they were considered contaminants, therefore were not processed further.

The 334 culture-positive samples yielded 351 bacterial

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Table 1. Frequency of Isolates from the Wound Samples Name of the isolate

Table 3. Antimicrobial Resistance Pattern of Gram-negative Bacterial Isolates Antimicrobial agents (in µg)

E. coli (n = 58) (%)

Pseudomonas (n = 30) (%)

Klebsiella (n = 24) (%)

Citrobacter (n = 11) (%)

11 (78.6)

8 (33.3)

5 (45.5 )

4 (28.6)

13 (92.9)

17 (70.8)

6 (54.5)

12 (85.7)

10 (71.4)

17 (70.8)

7 (63.6)

7 (50.0)

18 (60.0)

10 (71.4)

16 (66.7)

9 (81.8)

9 (64.3)

15 (50.0)

11 (78.6)

18 (75.0)

8 (72.7)

12 (85.7)

48 (82.8)

30 (100.0)

13 (92.3)

22 (91.7)

9 ( 81.8)

12 (85.7)

Ciprofloxacin

51 (87.9)

22 (73.3)

11 (78.6)

21 (87.5)

8 (72.7)

13 (92.9)

Piperacillin

46 (79.3)

13 (43.3)

13 (92.9)

14 (58.3)

9 (81.8)

10 (71.4)

Number of isolate (total number of isolates, n = 351)

%

Amikacin

12 (20.7)

12 (40.0)

Staphylococcus aureus

170

48.43

Ofloxacin

50 (86.2)

20 (66.7)

Escherichia coli

58

16.52

Ceftazidime

36 (62.1)

15 (50.0)

Pseudomanas spp.

30

8.55

Ceftriaxone

38 (65.5)

Coagulase-negative Staphylococcus

30

8.55

Gentamicin

40 (69.0)

Klebsiella spp.

24

6.84

Tetracycline

Proteus spp.

14

3.99

Citrobacter spp.

11

3.13

Acinetobacter spp.

14

3.99

Acinetobacter (n = 14) (%)

Proteus (n = 14) (%)

Table 4. Comparison of Antimicrobial Resistance Pattern to Gram-negative Bacteria with Two Other Similar Studies Table 2. Antimicrobial Resistance Pattern of Grampositive Bacterial Isolates

Antimicrobial agents

Pseudomonas spp.

A*

B*

C*

E. coli A

Klebsiella spp.

B

A

B

Acinetobacter A

B

Citrobacter A

B

Proteus spp.

A

B

S. aureus (n = 170) (%)

Coagulase-negative Staph. (n = 30) (%)

Amikacin

40.0

61.1

39.0

22.7

46.5

33.3

67.4

78.6

68.6

45.5

51.2

28.6

36.5

Ceftazidime

50.0

58.9

54.0

62.1

72.3

70.8

77.0

71.4

68.9

63.6

67.5

50.0

41.2

Ampicillin

124 (72.9)

21 (70.0)

Ceftriaxone

60.0

-

22.0

65.5

-

66.7

-

71.4

-

81.8

-

64.3

-

Cephalexin

138 (81.2)

11 (36.7)

Ciprofloxacin

73.3

59.3

58.0

87.9

86.6

87.5

51.9

78.6

65.7

72.7

67.5

92.9

44.4

Gentamicin

50.0

-

24.0

69.0

-

75.0

-

78.6

-

72.7

-

85.7

-

Antimicrobial agent

Ciprofloxacin

121 (71.2)

19 (63.3)

Azithromycin

102 (60.0)

19 (63.3)

Piperacillin

43.3

46.9

-

79.3

79.9

58.3

85.0

92.9

76.8

81.8

81.2

71.4

77.8

Netilmycin

-

55.9

-

-

39.5

-

62.6

-

40.3

-

40.7

-

31.7

Amikacin

41 (24.1)

5 (16.7)

Ceftriaxone

46 (27.1)

10 (33.3)

Tetracycline

56 (32.9)

8 (26.7)

Vancomycin

0 (0)

0 (0)

61 (35.9%)

8 (26.7)

Methicillin

Figures in the parentheses indicate percentage.

isolates out of which 317 had single pathogen and 17 had two pathogens each. Mixed growth of S. aureus and E. coli were present in 13 and S. aureus and Acinetobacter in four of these 17 samples. Two hundred out of the 351 isolates were gram-positive bacteria and rest 151 were gram-negative. S. aureus was the commonest organism present in 170 (48.43%) samples followed by E. coli in 58 (16.52%), Pseudomonas spp. and coagulase-negative Staphylococcus spp. in 30 samples (8.55%) each (Table 1).

The antimicrobial susceptibility and resistance pattern of bacterial isolates to various antibiotics are shown in Tables 2 and 3.

Discussion Infections caused by antimicrobial-resistant strains are worldwide problems. The increasing prevalence of multidrug-resistant organisms with few treatment options such as gram-negative bacilli and MRSA,

*A: Present study; B: Mohanty et al; C: Shampa et al.

both in hospitalized patients and in the community are causes for concern. This trend in antimicrobialresistant strains is true for infection at any site of the body including wound infections. S. aureus, E. coli and Pseudomonas species were the main pathogens detected in the present study. Similar organisms were also observed as main pathogens in wound samples as reported by Mohanty et al8 and Zargar et al.9

A very high rate of antibiotic resistance was seen with gram-negative bacterial isolates (Table 3). In these cases with E. coli, Proteus and Klebsiella, resistance against amikacin were comparatively less, so amikacin can still be used for the treatment of these infections.

We have observed a 35.9% prevalence rate of MRSA. Nearly similar prevalence has been reported by Goyal et al10 (37.3%), Rajaduraipandi11 (31.3%) and Srinivasan et al12 (33.3%). Maximum strains of S. aureus were resistant to ampicillin (72.9%) ciprofloxacin (71.2%), cotrimoxazole (94.7%), azithromycin (60%) and cephalexin (81.2%) in the present study (Table 2). High resistance to these drugs has also been reported by Shankar et al13 and Bradley et al.14 Least resistance was observed against amikacin (24.1%), ceftriaxone (27.1%) and tetracycline (32.9%). A good number of coagulasenegative staphylococci were also resistant to methicillin (26.7%). But all S. aureus and coagulase-negative staphylococcus strains were found to be 100% sensitive to vancomycin, which is the drug of choice for treating

For Pseudomonas, piperacillin and third-generation cephalosporins (ceftazidime and ceftriaxone) emerged as the most sensitive drugs. The resistance rate of piperacillin was 43.3%, as compared to ceftazidime (50%) and ceftriaxone (60%). But organisms other than Pseudomonas and Klebsiella have shown high percentage of resistance against piperacillin. Gentamicin also can be used in some selected cases with positive sensitivity reports. All organisms except Acinetobacter showed fairly low resistance against amikacin and it was very difficult to choose a proper antibiotic for the cases infected with Acinetobacter. Point to be noted that our study revealed quite high percentage of resistance against ciprofloxacin and tetracycline, two very common antimicrobials used in day-to-day

infections caused by MRSA. However, this antibiotic should not be used indiscriminately to prevent quick emergence of resistant strains among staphylococci.

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drug review

Original Study practice. Antimicrobial sensitivity pattern as found in similar studies by Mohanty et al8 and Shampa et al15 is shown in Table 4. Some variations in resistance pattern have been observed from place-to-place.

Conclusion Antimicrobial susceptibility pattern in this study suggested that drug therapy for wound infections should always be guided by the sensitivity report. Infected wounds, which do not respond to treatment, should be evaluated for the presence of multidrug-resistant organisms. Continuous surveillance is necessary to monitor antimicrobial resistance and antimicrobial policy should be updated according to the changing susceptibility pattern of bacteria.

References 1. Landis SJ. Chronic wound infection and antimicrobial use. Adv Skin Wound Care 2008;21(11):531-40; quiz 5412.

2. Forbes BA, Sahim DF, Weissfeld AS. In: Bailey and Scott’s Diagnostic Microbiology. 11th edition, Mosby Inc 2002: p.978-9.

3. Cooper RA. Understanding wound infections. Position document; University of Wales Institute, Cardiff (UK).

2-5.

4. Gales AC, Jones RN, Pfaller MA, Gordon KA, Sader HS. Two-year assessment of the pathogen frequency and antimicrobial resistance patterns among organisms isolated from skin and soft tissue infections in Latin American hospitals: results from the SENTRY antimicrobial surveillance program, 1997-98. SENTRY Study Group. Int J Infect Dis 2000;4(2):75-84.

5. Hartman BJ, Tomasz A. Low-affinity penicillin-binding protein associated with beta-lactam resistance in Staphylococcus aureus. J Bacteriol 1984;158(2):513-6.

6. Cruickshank R, Duguid JP, Marmion BP, Swain RHA. In: Medical Microbiology. 12th edition, Vol. 2, p.170-88.

7. NCCLS. Performance Standards for Antimicrobial Susceptibility Testing; Twelfth Informational Supplement.

NCCLS document M100-S12 (ISBN 1-56238-454-6).

NCCLS, 940 West Valley Road, Suite 1400,Wayne, Pennsylvania 19087-1898, USA, 2002. (General NCCLS website: http://www.nccls.org).

8. Mohanty S, Kapil A, Dhawan B, Das BK. Bacteriological and antimicrobial susceptibility profile of soft tissue infections from Northern India. Indian J Med Sci 2004;58(1):10-5.

9. Zargar AH, Masoodi SR, Laway BA, Wani AI, Bashir MI. Ciprofloxacin in the management of soft tissue infections in diabetes mellitus. J Assoc Physicians India 2000;48(7):757-8.

10. Goyal R, Das S, Mathur M. Colonisation of methicillin resistant Staphylococcus aureus among health care workers in a tertiary care hospital of Delhi. Indian J Med Sci 2002;56(7):321-4.

11. Rajaduraipandi K, Mani KR, Panneerselvam K, Mani M, Bhaskar M, Manikandan P. Prevalence and antimicrobial susceptibility pattern of methicillin resistant Staphylococcus aureus: a multicentre study. Indian J Med Microbiol 2006;24(1):34-8.

12. Srinivasan S, Sheela D, Shashikala, Mathew R, Bazroy J, Kanungo R. Risk factors and associated problems in the management of infections with methicillin resistant Staphylococcus aureus. Indian J Med Microbiol 2006;24(3):182-5.

13. Shankar CU, Harish BN, Kumar PMU, Navaneeth BV. Prevalence of methicillin resistant Staphylococcus aureus in JIPMER Hospital - a preliminary report. Indian J Med Microbiol 1997;15(3):137-8.

14. Bradley JM, Noone P, Townsend DE, Grubb WB. Methicillin-resistant Staphylococcus aureus in a London hospital. Lancet 1985;1(8444):1493-5.

15. Shampa A, Bhattacharjee A, Garg A, Sen MR. Antimicrobial susceptibility of Pseudomonas aeruginosa isolated from wound infections. Indian J Dermatol 2006;51(4):286-8.

Esomeprazole and Levosulpiride in Management of GERD Ajay Kumar

Abstract Gastroesophageal reflux disease (GERD) is the most common disease of the gastrointestinal tract. It may present as nonerosive disease, whereas others may have esophagitis, peptic strictures or Barrett’s esophagus. In primary care, patients are often treated empirically with symptom alleviation being the major goal of therapy. Histamine H2-receptor antagonist (H2RA) or a proton pump inhibitors (PPIs) are used as pharmacotherapy for acid suppression along with lifestyle modifications. Evidence clearly shows PPIs to be superior to H2RAs. Prokinetic agents have also been evaluated for the treatment of GERD and dyspepsia. Esomeprazole is a pure PPI isomer and so provides more effective and rapid acid control compared with other PPIs. Levosulpiride, a prokinetic drug has shown high efficacy in the control of dyspeptic symptoms with favorable safety profile. It has been shown that combination therapy with prokinetics is effective for patients dissatisfied with PPI monotherapy.

Combining prokinetics to a PPI improves treatment efficacy with greater symptomatic improvement than either drug used as monotherapy. Combination therapy also improves patient satisfaction.

Keywords: Gastroesophageal reflux disease, proton pump inhibitor, prokinetic, combination

G

astroesophageal reflux disease (GERD) is the most common disease of the gastrointestinal tract.1 It is a consequence of the failure of the normal antireflux barrier to protect against frequent and abnormal amounts of gastroesophageal reflux. Most patients have no visible mucosal damage at the time of endoscopy (nonerosive GERD), whereas others have esophagitis, peptic strictures or Barrett’s esophagus.

The pathogenesis of GERD is complex, resulting from an imbalance between defensive factors protecting the esophagus (antireflux barriers, esophageal acid clearance, tissue resistance) and aggressive factors refluxing from the stomach (gastric acidity, volume and duodenal contents).2

The typical clinical symptoms of GERD are heartburn (burning sensation in the chest accompanied by pain) and regurgitation (sour and bitter taste on the tongue).3 Atypical presentations may include noncardiac chest pain, asthma, cough, aspiration pneumonia or globus and laryngitis in patients with or without typical symptoms of GERD.1

Senior Consultant Dept. of Gastroenterologist and Hepatologist Indraprastha Apollo Hospital, New Delhi

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The major risk factors for GERD include obesity, high fat diet, too much eating, spicy food, smoking, tight clothing, emotional stress, regular fast food, tea and coffee, pregnancy, drugs and habit of lying down immediately after eating.3 The rationale for GERD therapy depends on a careful definition of specific aims. In patients without esophagitis, the therapeutic goals are to relieve reflux symptoms and prevent frequent symptomatic relapses.

In patients with esophagitis, the goals are to relieve symptoms and heal esophagitis while preventing further relapses and complications.2 In patients with GERD, treatment is directed at acid suppression through the use of lifestyle modifications (e.g., elevating the head of the bed, modifying the size and composition of meals) and pharmacologic agents: Histamine H2-receptor antagonist (H2RA) or a proton pump inhibitor (PPI). The efficacy of antisecretory drugs in healing GERD depends on the strength and duration of acid suppression within a 24-hour period, and the duration of the treatment.4 There is a large body of evidence that shows PPIs to be clearly superior to H2RAs. Over the years, prokinetic agents have also been evaluated for the treatment of GERD and dyspepsia.

In primary care, patients are often treated empirically;

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Drug Review

Drug Review treatment choices are driven largely by symptoms, with the aim of reducing those symptoms to the point where they become minimal or disappear.5 Proton pump inhibitors Proton pump inhibitors (PPIs) are antisecretory drugs, which suppress the final step in gastric acid secretion by binding to the proton pump (H+/K+-ATPase enzyme system) on the gastric parietal cell. Despite the relatively short elimination half-lives of PPIs, their irreversible binding to the proton pump allows for a long duration of acid suppression and once-daily dosing in most patients.6 The postprandial acid inhibition produced by H2RAs is only partial. On the contrary, PPIs are able to inhibit meal-induced acid secretion. Besides elevating gastric pH, PPIs also reduce 24-hour intragastric volume, facilitating gastric emptying and reducing refluxate volume.7 PPIs have superior efficacy compared with H2RAs on the basis of their ability to maintain an intragastric pH >4 from 10 to 14 hours daily compared with around 6-8 hours daily with the H2RAs.2 Well-controlled clinical trials have demonstrated PPIs to be the most effective available option in the acute treatment of GERD and in maintenance therapy. In a meta-analysis, the mean overall healing proportion irrespective of drug dose or treatment duration (≤12 weeks) was highest with PPIs (83.6% ± 11.4%) versus H2RAs (51.9% ± 17.1%), sucralfate (39.2% ± 22.4%) or placebo (28.2% ± 15.6%). PPIs showed significantly faster healing rate (11.7%/week) versus H2RAs (5.9%/week) and placebo (2.9%/week). PPIs provided faster, more complete heartburn relief (11.5%/week) versus H2RAs (6.4%/week). It was concluded that PPIs achieve more complete esophagitis healing and heartburn relief versus H2RAs and occurs nearly twice as fast.6,8

Esomeprazole (S-omeprazole), an enantiomer of the racemate omeprazole, is the first PPI to be developed as an isomer.10 Being a pure PPI isomer, it produces higher blood levels than the racemic mixtures, leading to an increase in gastric acid suppression, which is associated with a small, but significant increase in healing rates for erosive esophagitis.11 It is a powerful inhibitor of gastric acid: Can totally abolish HCl secretion, both resting as well as stimulated by any of the secretagogues, without much effect on pepsin, intrinsic factor, juice volume and gastric motility. Single 20-40 mg oral doses generally give rise to peak plasma esomeprazole concentrations of 0.5-1.0 mg/l within 1-4 hours, but after several days of once-daily administration these levels may increase by about 50%. Potential advantages of this drug include once-daily dosing, an absence of significant adverse reactions, a well-tolerated side effect profile and a cost-effective average wholesale price. Interpatient variability in acid inhibition appears to be lower with esomeprazole when compared to other PPIs.12 Esomeprazole inhibits acid production faster than other PPIs and, as a result, there is faster symptom relief.7 It can be used for ‘on-demand’ or as needed symptomatic treatment for symptoms associated with GERD. This indication allows patients the freedom to take medication when GERD symptoms appear and could be more cost-effective.12 ÂÂ

Prokinetic agents Prokinetic drugs have potential usefulness as adjunctive treatment of GERD. Randomized controlled trials provide moderate-quality evidence that prokinetic drugs improve symptoms in patients with reflux esophagitis and low-quality evidence that they have an impact on endoscopic healing.9 These drugs improve reflux symptoms by increasing lower esophageal sphincter (LES) pressure, acid clearance or gastric emptying.2

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provided greater acid control in more patients and maintained intragastric pH >4 for a longer period than lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg and rabeprazole 20 mg in patients with symptoms of GERD. Higher 24-hour median pH and a higher proportion of patients with intragastric pH > 4 for ≥ 12 hours and 16 hours were reported with esomeprazole 40 mg once-daily than with all the other PPIs in each study.15

Esomeprazole, the first pure PPI isomer

ÂÂ

In patients with GERD, standard doses of esomeprazole maintain intragastric pH >4 for significantly longer periods compared with standard doses of other PPIs after five days of treatment as shown in a randomized, open-label, comparative five-way crossover study. On Day 5, intragastric pH was maintained above 4.0 for a mean of 14.0 hours with esomeprazole, 12.1 hours with rabeprazole, 11.8 hours with omeprazole, 11.5 hours with lansoprazole and 10.1 hours with pantoprazole (p ≤ 0.001 for differences between esomeprazole and all other comparators). Esomeprazole also provided a significantly higher percentage of patients with an intragastric pH >4.0 for >12 hours versus other PPIs (p < 0.05). The study concluded that esomeprazole at the standard dose of 40 mg once-daily provided more effective control of gastric acid at steady state than standard doses of other PPIs in patients with symptoms of GERD.13,14 In four randomized crossover studies in patients with symptoms of GERD, esomeprazole 40 mg

ÂÂ

ÂÂ

In another comparative study, esomeprazole was more effective than omeprazole, lansoprazole and pantoprazole in providing rapid relief of heartburn symptoms and acid reflux symptoms in patients with reflux esophagitis.16 Other studies too have found the newest PPI esomeprazole 40 mg superior to omeprazole 20 mg and to lansoprazole 30 mg in healing esophagitis.17,18

Levosulpiride Levosulpiride is a sulpiride isomer that exerts its prokinetic action through a dual mechanism: As a D2 dopamine receptor antagonist and as a serotonin 5-hydroxytryptamine receptor 4 (5-HT4) agonist, which confer a cholinergic effect.19 Being a selective dopamine D2-receptor antagonist with prokinetic activity, it is a therapeutic option in the management of functional dyspepsia on the basis of dopaminergic pathways controlling gastrointestinal motility; while, the serotonergic (5-HT4) component of levosulpiride enhances its therapeutic efficacy in functional dyspepsia.20 Levosulpiride is safe and effective in the treatment of dysmotility-like functional dyspepsia and nonerosive reflux disease (NERD). In a prospective, openlabel, multicenter 4-week trial in 342 patients with dysmotility-like functional dyspepsia and NERD, treatment with levosulpiride 25 mg thrice-daily orally resulted in >50% decrease in the global symptom score. At the 30-day visit, all symptoms had almost disappeared, a trend that was maintained until the last visit.20 A double-blind multicentric study carried out in 45 Italian Gastroenterology Departments evaluated the efficacy and safety of levosulpiride in short-term treatment of patients with functional dyspepsia. Patients were randomly assigned to either levosulpiride (25 mg t.i.d.), domperidone (10 mg t.i.d.), metoclopramide (10 mg t.i.d.) or placebo (1 tablet t.i.d.) for four weeks. Significant improvement was recorded for all symptoms at Days 10 and 28 in all groups

(p < 0.001), but levosulpiride was significantly (p < 0.01) superior to domperidone, metoclopramide and placebo both in the overall clinical improvement scale as well as in a subgroup of symptoms (postprandial bloating, epigastric pain, heartburn).21 Levosulpiride has a good safety profile and the frequency of adverse events is similar to that of other D2 dopamine antagonists. Therefore, it is a useful therapeutic option in the management of patients with functional dyspepsia, as well as in those with delayed gastric emptying.19 PPI and prokinetic: Rationale of combination PPIs decrease acid production and exhibit high healing rates and rates of resolution of reflux symptoms at four weeks, but they are of no help in improving the underlying disturbance in gut motility or improve tone of cardiac sphincter; relapse is common. Prokinetic agents increase the tone of the LES and enhance upper gastrointestinal tract motility. They therefore act on one of the pathophysiological mechanisms of GERD. In terms of symptom improvement, prokinetics noticeably have an edge over others in functional dyspepsia (46% over 20% for antisecretory agents) with superior results.

Conversely, prokinetics do not promote healing of esophagitis and so cannot be considered as an adequate treatment for GERD.22 Few studies have demonstrated that addition of prokinetic with antisecretory agent decreases relapse rates in GERD patients when compared to antisecretory agent alone. The combination is synergistic by decreasing acid production as well as increasing lower esophageal tone and esophageal clearance thus producing a better therapeutic response.22 PPIs are unstable at a low pH, dysmotility will slow down gastric emptying, resulting in retention of PPIs. Retention of PPIs inside the stomach for a long time may result in an impaired acid suppressive effect, so rapid transit of the PPIs to the upper intestine will be of benefit. Hence, combining PPIs with prokinetics will improve the effect of PPIs.3,23 It has been shown that combination therapy with prokinetics is effective for patients dissatisfied with PPI monotherapy.23 NERD is a more difficult to treat than reflux esophagitis due to the high prevalence of PPI resistance. The efficacy of additional prokinetics for PPI-resistant NERD was observed as significant improvement in total score by Miyamoto et al.24 Giving prokinetic together with PPI for GERD will have better results than by giving PPI alone.3

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Drug Review

Drug Review The therapeutic effectiveness of levosulpiride associated with omeprazole versus omeprazole alone in the reflux esophagitis was evaluated in a study.

While no difference was shown in terms of macro- and microscopic resolution, a better subjective relief was obtained in the group treated with the combination of levosulpiride and omeprazole.25 Conclusion GERD is among the most prevalent of gastrointestinal disorders. The relief of symptoms and the long-term control of the disease are the primary aims of therapy for the majority of patients. PPIs are more effective for acid-related symptoms and higher endoscopic healing rates in comparison with H2RAs.4 Esomeprazole is a new PPI that provides more effective acid control compared with other PPIs.13 Once-daily oral esomeprazole 40 mg demonstrates greater antisecretory activity than other PPIs. Overall, in clinical trials of four weeks’ to 6 months’ duration in patients with GERD, esomeprazole had similar or better efficacy than other agents.26 Patients benefit from the more rapid symptom relief, higher rates of healing of erosive esophagitis and improved maintenance of healing that can be achieved with esomeprazole.13 Levosulpiride is a prokinetic drug. Studies have demonstrated its high efficacy in the control of dyspeptic symptoms and favorable safety profile;20 in comparative studies the effect of levosulpiride is similar or superior to that of other dopamine antagonists.19 Adding prokinetics to a PPI therefore improves treatment efficacy with greater symptomatic improvement than either drug used as monotherapy. Patients require less number of oral medications and it reduces the rates of recurrence of symptoms. Moreover, combination therapy also improves patient satisfaction.

References 1. Liu JJ, Saltzman JR. Management of gastroesophageal reflux disease. South Med J 2006;99(7):735-41; quiz 742, 752.

2. Richter JE, Friedenberg FK. Gastroesophageal Reflux Disease. Chapter 43. In: Feldman: Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. Feldman, Friedman, Brandt (Eds.), 9th edition, Elsevier: Saunders 2010:p.705-26.

3. Ndraha S. Combination of PPI with a prokinetic drug in gastroesophageal reflux disease. Acta Med Indones 2011;43(4):233-6.

4. Hrelja N, Zerem E. Proton pump inhibitors in the management of gastroesophageal reflux disease. Med Arh 2011;65(1):52-5.

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5. Looijer-van Langen M, Veldhuyzen van Zanten S. Does the evidence show that prokinetic agents are effective in healing esophagitis and improving symptoms of GERD? Open Med 2007;1(3):e181-3.

6. McCarthy DM, Caspi A. Proton pump inhibitors in the management of patients with acid-peptic disorders: a managed care perspective. P & T 2005;30(5):282-91.

7. Guimarães EV, Guerra PV, Penna FJ. Management of gastroesophageal reflux disease and erosive esophagitis in pediatric patients: focus on delayed-release esomeprazole.

Ther Clin Risk Manag 2010;6:531-7.

8. Chiba N, De Gara CJ, Wilkinson JM, Hunt RH. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: a meta-analysis.

Gastroenterology 1997;112(6):1798-810.

9. Manzotti ME, Catalano HN, Serrano FA, Di Stilio G, Koch MF, Guyatt G. Prokinetic drug utility in the treatment of gastroesophageal reflux esophagitis: a systematic review of randomized controlled trials. Open Med 2007;1(3): e171-80.

19. Serra J. Levosulpiride in the management of functional dyspepsia and delayed gastric emptying. Gastroenterol Hepatol 2010;33(8):586-90.

20. Lozano R, Concha MP, Montealegre A, de Leon L, Villalba JO, Esteban HL, et al. Effectiveness and safety of levosulpiride in the treatment of dysmotility-like functional dyspepsia. Ther Clin Risk Manag 2007;3(1): 149-55.

21. Corazza GR, Biagi F, Albano O, Bianchi Porro G, Cheli R, Mazzacca G, et al. Levosulpiride in functional dyspepsia: a multicentric, double-blind, controlled trial. Ital J Gastroenterol 1996;28(6):317-23.

22. Khajuria DK, Vinod K, Razavi M, Karimian H, Pradeep S. Gastroesophageal reflux disease: a review of superior effects of proton pump inhibitors and prokinetic agents as a combination therapy versus monotherapy.

Pharmacologyonline 2011;3:701-5.

23. Miyamoto M, Haruma K, Takeuchi K, Kuwabara M.

Frequency scale for symptoms of gastroesophageal reflux disease predicts the need for addition of prokinetics to proton pump inhibitor therapy. J Gastroenterol Hepatol 2008;23(5):746-51.

24. Miyamoto M, Manabe N, Haruma K. Efficacy of the addition of prokinetics or proton pump inhibitor (PPI) resistant non-erosive reflux disease (NERD) patients: significance of frequency scale for the symptom of GERD (FSSG) on decision of treatment strategy. Intern Med 2010;49(15):1469-76.

25. Dallera F, Scanzi G, Gendarini A, Jezzi B. The efficacy of the omeprazole-levosulpiride combination in the therapy of distal reflux esophagitis. Minerva Med 1992;83(9): 541-3.

26. McKeage K, Blick SK, Croxtall JD, Lyseng-Williamson KA, Keating GM. Esomeprazole: a review of its use in the management of gastric acid-related diseases in adults.

Drugs 2008;68(11):1571-607.

10. Morgner-Miehlke A, Petersen K, Miehlke S, Labenz J. Esomeprazole: potent acid suppression in the treatment of acid-related disorders. Expert Rev Clin Immunol 2005;1(4):511-27.

11. Armstrong D. New pharmacologic approaches in gastroesophageal reflux disease. Gastroenterol Clin North Am 2010;39(3):393-418.

12. Kulkarni S, Tripathi S, Mehta PD, Lodhi NS, Sengar NP. Esomeprazole in the treatment of acidic disorder: an overview. Asian J Biochem Pharm Res 2011;2(1):562-6.

13. Beck J. Efficacy of esomeprazole in patients with acidpeptic disorders. Gastroenterol Nurs 2004;27(2):44-9.

14. Miner P Jr, Katz PO, Chen Y, Sostek M. Gastric acid control with esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole: a five-way crossover study. Am J Gastroenterol 2003;98(12):2616-20.

15. Röhss K, Lind T, Wilder-Smith C. Esomeprazole 40 mg provides more effective intragastric acid control than lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg and rabeprazole 20 mg in patients with gastrooesophageal reflux symptoms. Eur J Clin Pharmacol 2004;60(8):531-9.

16. Zheng RN. Comparative study of omeprazole, lansoprazole, pantoprazole and esomeprazole for symptom relief in patients with reflux esophagitis. World J Gastroenterol 2009;15(8):990-5.

17. Richter JE, Kahrilas PJ, Johanson J, Maton P, Breiter JR, Hwang C, et al. Efficacy and safety of esomeprazole compared with omeprazole in GERD patients with erosive esophagitis: a randomized controlled trial. Am J Gastroenterol 2001;96(3):656-65.

18. Castell DO, Kahrilas PJ, Richter JE, Vakil NB, Johnson DA, Zuckerman S, et al. Esomeprazole (40 mg) compared with lansoprazole (30 mg) in the treatment of erosive esophagitis. Am J Gastroenterol 2002;97(3):575-83.

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Clinical Practice

clinical practice

Neonatal Conjunctivitis: The Joint Responsibility of Obstetricians, Pediatricians and Ophthalmologists Harpal Singh Jhagta

Abstract Neonatal conjunctivitis or ophthalmia neonatorum is an ocular emergency leading to blindness. The major culprit bacteria are Chlamydia trachomatis and Neisseria gonorrhoeae, which are acquired through the infected birth canal of mother. Early treatment of maternal genital tract infections, good perinatal care, immediate ocular prophylaxis and early recognition followed by prompt ophthalmic consultation may be sight-saving for the newborn.

Keywords: Ophthalmia neonatorum, Chlamydia trachomatis, Neisseria gonorrhoeae, genital tract infections

N

eonatal conjunctivitis or ophthalmia neonatorum is an ocular emergency leading to blindness in approximately 10,000 babies annually worldwide.1 It is defined as any conjunctivitis occurring in the first four weeks after birth.2 It can be chemical, bacterial or viral in etiology. The causative organisms are acquired mainly through infected birth canal and only a small percentage of them are acquired by other ways. Although simple investigations like Gram and Giemsa staining suffice, the precise identification of causative organism is necessary due to potentially life-threatening systemic complications and severe ocular morbidity particularly with Chlamydia trachomatis and Neisseria gonorrhoeae.3 Early treatment of maternal genital tract infections, good perinatal care, immediate ocular prophylaxis and early recognition followed by prompt ophthalmic consultation may be sight-saving for the newborn.

The epidemiology of neonatal conjunctivitis has changed markedly after introduction of 1% silver nitrate solution (Credeâ&#x20AC;&#x2122;s method) as a prophylaxis against gonococcal conjunctivitis. Previously, gonococcal conjunctivitis was the commonest form, which underwent significant downfall with the advent of Credeâ&#x20AC;&#x2122;s method in UK, Europe and United States.4 One percent silver nitrate

Dept. of Ophthalmology Ganga Devi Pandey Eye Hospital Mohendergarh, Haryana

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is not used now a days as it is not effective against Chlamydia and causes chemical conjunctivitis within first 36 hours after birth. This has now been replaced by erythromycin or tetracycline eye ointment. Chemical conjunctivitis due to silver nitrate is self-limiting and may rarely cause lacrimal punctal stenosis.

INFECTIOUS ETIOLOGY The major culprit bacteria are C. trachomatis and N. gonorrhoeae, which are acquired through the infected birth canal of mother. The predisposing factors are premature rupture of membranes and prolonged labor as the duration of labor is an important factor in the development of disease. Neonatal conjunctivitis after cesarean section may be due to intrauterine infection by Chlamydia secondary to premature rupture of membranes 5 or transplacental transfer of the organism.6 C. trachomatis is the most frequent cause of neonatal conjunctivitis in United States. Infants of mothers with untreated chlamydial infections have a 30-40% chances of developing conjunctivitis and 10-20% chances of developing pneumonia.7 The incubation period ranges from 5 to 14 days and may present unilaterally or bilaterally with watery or mucopurulent discharge, lid edema, papillary conjunctival response and pseudomembrane formation. However, the course is mild and self-limiting; severe infection may result in conjunctival scarring, punctal stenosis and corneal pannus formation. Chlamydial pneumonia may be lifethreatening.

Gonococcal conjunctivitis is more severe than chlamydial conjunctivitis. It is characterized by development of hyperacute conjunctivitis within 24-48 hours after birth showing marked lid edema, chemosis and copious purulent discharge, which tends to reaccumulate immediately after cleaning. It can penetrate the intact corneal epithelium causing corneal perforation and endophthalmitis within a short span of time.8 Systemic dissemination may lead to stomatitis, arthritis, rhinitis, septicemia and meningitis.

Other bacterial causes include Staphylococccus aureus, Streptococcus pneumoniae, Haemophilus, Escherichica coli, Klebsiella and Pseudomonas. Pseudomonas can also penetrate the intact corneal epithelium.

Herpes simplex keratoconjunctivitis usually occurs within 3-15 days and may be caused by both herpes simplex virus (HSV-1) and HSV-2. HSV-2 is more resistant to treatment and usually presents with generalized infection.

effective against Chlamydial infections. Recent studies suggest superior bactericidal effects along with activity against herpes virus with the instillation of 2.5% povidone-iodine drops.10 TREATMENT Neonatal conjunctivitis is an emergency so along with the ophthalmologist, the obstetrician and pediatrician should also be well aware of the condition and early referral is warranted. As the causative organism is sexually transmitted, it is vital to treat mother and her sexual partner. It is important to treat the infants with systemic rather than topical drugs to prevent systemic dissemination of the organism. Current World Health Organization (WHO) guideline for the management of sexually transmitted infections recommends that all cases of neonatal conjunctivitis should be treated for both N. gonorrhoeae and C. trachomatis. The co-infection rates are estimated to be 2%.

LABORATORY DIAGNOSIS Ophthalmia neonatorum is essentially a clinical diagnosis; however, conjunctival scrappings for Gram and Giemsa staining should be taken from all cases for the precise identification of the causative agent.

Gonococci appear as intracellular gram-negative diplococci on Gram-staining. Chocolate agar and Thayer Martin media can be used to isolate the organism.

Infection

Treatment

Chlamydia

Oral erythromycin syrup 50 mg/kg/day in four divided doses for two weeks.

Infected partners should receive oral doxycycline 100 mg b.i.d. for one week or single dose of azithromycin 1 g.

Gonococci

Chlamydia appears as intracytoplasmic inclusion bodies on Giemsa staining in 60-80% cases. Direct immunofluorescent monoclonal antibody assay and polymerase chain reaction (PCR) are other rapid and sensitive techniques available.9

Penicillin G drops 10,000-20,000 units hourly and IV penicillin G drops 1 lac units/ kg/day in 4 divided doses for 1 week.

Ceftriaxone IV or IM 25-50 mg/kg/day oncedaily for 1 week.

Frequent ocular irrigation with normal saline.

Gram-staining and cultures on blood agar may help to identifying other bacteria.

Other gramGentamicin/Tobramycin eye ointment positive bacteria 4-6 times a day.

The diagnosis of herpes infections is made by identification of multinucleate giant cells and eosinophilic intranuclear inclusion bodies on smears, positive viral cultures or positive monoclonal antibody immunoassays.

Gram-positive bacteria

Erythromycin 0.5% ointment four times a day.

Viral

Trifluridine drops 6 times a day or vidarabine ointment for 1 week.

PROPHYLAXIS Early treatment of maternal genital tract infection carries a top priority in the prophylactic measures against neonatal conjunctivitis. Occurrence of chemical conjunctivitis has reduced the use of 1% silver nitrate solution and it is being replaced by instillation of erythromycin and tetracycline ointments immediately after birth at most places. However, none of them is

CONCLUSION Neonatal conjunctivitis is a preventable cause of blindness. Active efforts in treating pregnant women for sexually transmitted infections prior to delivery, mandatory prophylaxis for all newborns immediately after birth, proper hygiene and good neonatal care can markedly reduce the burden of childhood blindness in developing countries.

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case report

clinical practice REFERENCES 1. Isenberg SJ, Apt L, Wood M. The influence of perinatal infective factors on ophthalmia neonatorum. J Pediatr Ophthalmol Strabismus 1996;33(3):185-8.

2. Fransen L, Klauss V. Neonatal ophthalmia in the developing world. Epidemiology, etiology, management and control. Int Ophthalmol 1988;11(3):189-96.

3. Barry WC, Teare EL, Uttley AH, Wilson SA, McManus TJ, Lim KS, et al. Chlamydia trachomatis as a cause of neonatal conjunctivitis. Arch Dis Child 1986;61(8):797-9.

4. Schaller UC, Klauss V. Is Crede’s prophylaxis for ophthalmia neonatorum still valid? Bull World Health Organ 2001;79(3):262-3.

5. Mihile M, Deorari AK, Satpathy G, Sharma A, Singh M. Microbiological study of neonatal conjunctivitis with special reference to Chlamydia trachomatis. Indian J Ophthalmol 2002;50(4):295-9.

6. Shariat H, Young M, Abedin M. An interesting case presentation: a possible new route for perinatal acquisition of Chlamydia. J Perinatol 1992;12(3):300-2.

7. Harrison JR, English MG, Lee CK, Alexander ER. Chlamydia trachomatis infant pneumonitis: comparison with matched controls and other infant pneumonitis.

N Engl J Med 1978;298(13):702-8.

8. Sanders LL Jr, Harrison HR, Washington AE. Treatment of sexually transmitted chlamydial infections. JAMA 1986;255(13):1750-6.

9. Goroll AH, Mulley AG, May LA. Primary care medicine office evaluation and management of the adult patient.

4th edition, Lippincott, Williams & Wilkins: Phildelphia 2000:p.742.

10. Isenberg SJ, Apt L, Wood M. A controlled trial of povidoneiodine as prophylaxis against ophthalmia neonatorum.

New Engl J Med 1995;332(9):562-6.

A Rare Case of Chorangiosis of Placenta: An Important Placental Sign of Neonatal Morbidity and Mortality Sandhya Mittal*, Anupama Goel**, Bal Krishan Taneja†, Meenu Puri‡

Abstract Chorangiosis is a placental vascular lesion diagnosed histologically; involving terminal villi and is associated with a number of fetomaternal and placental conditions. It is a rare but ominous condition resulting in higher incidence of perinatal morbidity and mortality though the ultimate mechanism by which chorangiosis is involved in adverse perinatal outcomes is unknown.

We report a case with this unusual condition in association with major congenital malformations and perinatal mortality; thus re-emphasizing the need of complete placental examination including histopathological examination in all cases of perinatal mortality.

Keywords: Chorangiosis, hypoxia, placenta, perinatal, terminal villi

P

athological examination of placenta is probably the most underutilized pathologic assessment of any human tissue. The placenta provides a wealth of information retrospectively about the fetus and prospectively regarding the infant; often it gives useful insight for the diagnosis and treatment of sick newborns and reflects the impact of maternal disorders on pregnancy.

The normal chorionic villi should not contain more than five vascular channels even when the same vessel is present in more than one plane of section.

Chorangiosis is a placental change characterized by hypervascular terminal chorionic villi without stromal hypercellularity.1 It is an important sign of placental malperfusion and long-standing fetal hypoxia. The reported associated perinatal mortality and major congenital malformation have been as high as 42% and 39%, respectively.2 We report an unusual case of chorangiosis of placenta associated with major *Assistant Professor **Associate Professor †Professor ‡Resident (2nd Year) Dept. of Obstetrics and Gynecology MMIMSR, Mullana, Ambala, Haryana Address for correspondence Dr Sandhya Mittal 344/5, Urban Estate, Kurukshetra, Haryana - 136 118 E-mail: sandhya81969@yahoo.com

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congenital malformations in fetus and its bearing on the subsequent pregnancy.

Case report A 26-year-old G2P1L0 presented in the OPD at 29 weeks of gestation for antenatal check-up. She had a previous history of stillbirth delivered at home. Her general condition was good, vitals were stable and obstetric examination was normal for the gestational age. Her routine investigations were within normal limits; however, obstetric ultrasonography showed single, live intrauterine pregnancy of 27 weeks of gestation with bilateral renal agenesis and oligohydramnios. Placenta was fundoanterior with Grade 2 maturity. Fetal Echo showed findings suggestive of tetralogy of Fallot.

Guarded fetal prognosis was explained to the patient and pregnancy was continued. She had a full-term vaginal delivery; however, the baby was congenitally malformed and died within few hours of birth. Placenta was grossly unremarkable and weighed 640 g.

Bystanders refused to give consent for autopsy; however, the placenta was sent for histopathological examination, which revealed chorangiosis of placenta.

She conceived spontaneously after six months and underwent regular antenatal check-up. Her antenatal period was uneventful and she was taken up for elective cesarean section at 37 weeks of gestation and

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case report delivered a healthy baby weighing 3.4 kg with an Apgar score 8 and 9 at one and five minutes, respectively.

Histopathological examination of placenta revealed no abnormality. Her postnatal period was uneventful.

Discussion The placenta is the largest organ of fetal origin and pivotal not only for the proper fetal development but also both maternal and fetal functions. Therefore, histological examination of the placenta provides useful information in cases of poor obstetric outcome.

Three benign, inter-related vascular lesions have been identified in the placenta namely, chorangiosis, chorangiomatosis and chorangioma. Gestational age distribution is different for these vascular lesions with chorangioma and chorangiomatosis usually occurring before 32 weeks of gestation and chorangiosis more commonly seen after 37 weeks of gestation. The pathogenesis of these vascular lesions is unclear and the histological features especially those of chorangiosis and chorangiomatosis frequently overlap.

Placental chorangiosis is a vascular hyperplasia in the terminal chorionic villi, diagnosed histologically using the criteria described by Altshuler in 1984, as the presence of a minimum of 10 villi, each with â&#x2030;Ľ10 vascular channels in â&#x2030;Ľ10 areas of â&#x2030;Ľ3 random noninfarcted placental areas, when using 10 times magnification.2 Chorangiosis has been reported in 5-7% of placenta from infants who required admission to a newborn intensive care unit but the clinical importance of this pathological finding has not been studied extensively.3 The true etiology has not been identified but it has been proposed to result from hypoxia-related angiogenesis due to various maternal, fetal and placental disorders.1-4 The incidence of chorangiosis is higher in women living in high altitudes and thus a hypoxic stimulus may well lead to an extensive villous capillary and to connective tissue proliferative activity.

The associated maternal conditions include preeclampsia, eclampsia, diabetes mellitus, drug ingestion, urinary tract infection, severe anemia and syphilis.

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Placental conditions associated with chorangiosis include umbilical cord anomalies, single umbilical artery, abruption placenta, placenta previa, amnion nodosum and villitis (rubella virus, cytomegalovirus, syphilis and bartonella species are known to infect and induce proliferation of endothelial cells). An abnormal placenta could decompensate acutely leading to a catastrophic outcome.5 The fetal factors commonly associated with chorangiosis are the presence of major congenital anomalies, intrauterine growth retardation, intrauterine death and Apgar <5 at birth. The rate of recurrence of this lesion and its effect on the future pregnancies is unknown.

Conclusion In our case, chorangiosis of placenta was associated with major congenital malformation and adverse perinatal outcome but without any effect on the future pregnancy. Thus, we conclude that though the clinical significance of this pathological finding has not been reported extensively, it should be considered as a placental sign of potential clinical significance and should be mentioned in the pathology report of the patient.

References 1. De La Ossa MM. Cabello-Inchausti B, Robinson MJ. Placental chorangiosis. Arch Pathol Lab Med 2001;125(9): 1258.

2. Altshuler G. Chorangiosis. An important placental sign of neonatal morbidity and mortality. Arch Pathol Lab Med 1984;108(1):71-4.

3. Ogino S, Redline RW. Villous capillary lesions of the placenta: distinction between chorangioma, chorangiomatosis and chorangiosis. Hum Pathol 2000;31(8): 945-54.

4. Gupta R, Nigam S, Arora P, Khurana N, Batra S, Mandal AK. Clinico-pathological profile of 12 cases of chorangiosis. Arch Gynecol Obstet 2006;274(1):50-3.

5. Franciosi RA. Placental pathology casebook. Chorangiosis of the placenta increases the probability of perinatal mortality. J Perinatol 1999;19(5):393-4.

case report

Kikuchi Disease in an Uncommon Age and Site SHALINEE RAO*, AMUDHA JANAKI**, CN SAI SHALINI†, SANDHYA SUNDARAM‡

Abstract We present a case of Kikuchi disease involving axillary lymph nodes in a 67-year-old lady. This case highlights the occurrence of Kikuchi disease in an elderly individual at an uncommon location.

Keywords: Age, Kikuchi disease, axillary lymph node

K

ikuchi-Fujimoto disease (KFD) is a distinct clinicopathological entity with a benign course in general. The other synonyms for this condition include histiocytic necrotizing lymphadenitis, focal histiocytic lymphadenitis and subacute necrotizing lymphadenitis.1 We document here an interesting case of Kikuchi disease (KD) in a rare location affecting an uncommon age group.

Case Report

An excision biopsy of the lymph node was done to rule out tuberculosis. Grossly, lymph node measured 3.5 × 2.5 × 1 cm. Cut surface was homogeneous and grey-white (Fig. 1).

Microscopic examination of the lymph node showed multiple areas of necrosis predominantly in paracortical zone surrounded by histiocytes, immunoblasts Table 1. Hemogram

A 67-year-old lady presented with swelling in the left axilla associated with pain for two weeks and fever of one week duration. She also gave a history of slight loss of weight and appetite. On examination, 3.5 × 3 cm tender swelling was felt in the left axilla. Breast examination was normal. No other group of lymph nodes was palpable.

Total count

Laboratory investigations showed leukopenia and anemia (Table 1). Peripheral blood smear showed reactive lymphocytosis. No atypical cells or hemoparasites were seen on blood smear examination.

Fine-needle aspiration cytology (FNAC) of the axillary node revealed a reactive process.

*Associate Professor **Final Year Postgraduate †Assistant Professor ‡Professor Dept. of Pathology Sri Ramachandra University, Porur, Chennai Address for correspondence Dr Shalinee Rao Associate Professor, Dept. of Pathology Sri Ramachandra University, Porur, Chennai - 116 E-mail: shalineerao@rediffmail.com

Hemoglobin Platelets

3,990 cells/mm3 11 g/dl 2.33 lakhs/mm3

Packed cell volume

36.6

Polymorph

48%

Lymphocyte

45%

Eosinophil

1%

Monocyte

5%

Basophil

1%

Figure 1. Cut section of lymph node appears grey-white and homogeneous.

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case report

case report Discussion

Figure 2. Microscopic examination show pale necrotic areas surrounded by histiocytes and immunoblasts (H&E X 40); inset showing histiocytes, immunoblasts and karyorrhectic bodies (H&E X 400)

Figure 3. Necrotic areas showing numerous karyorrhectic bodies (H&E X 200).

Figure 4. Adjacent area in the lymph node showing multiple lymphoid follicles with germinal centers and congestion

and few plasmacytoid mononuclear cells (Fig. 2).

The necrotic areas showed numerous karyorrhectic bodies (Fig. 3). Congestion and lymphoid follicles with germinal centers were also noted (Fig. 4). Special stains for fungus and acid-fast bacilli were negative. A finaldiagnosis of necrotizing lymphadenitis favoring KD was made on histopathology.

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Kikuchi-Fujimoto disease (KFD) is an uncommon disease having a worldwide distribution with a slightly higher prevalence in Asian population.2 It is a benign self-resolving disorder, affecting more commonly young women. In adults, KD occurs more commonly in females while in children it is the reverse.3,4 The disease evolves over 2-3 weeks with tender cervical lymphadenopathy being a consistent feature. Lymph node can vary in size and enlarge upto 6 cm in size. Rarely, it may result in a generalized lymphadenopathy. Clinical manifestations vary with cervical lymphadenopathy, fever, weight loss, loss of appetite, nausea, vomiting, diarrhea, chest pain, splenomegaly and hepatomegaly. Involvement of extranodal sites is rare with involvement of skin, eye, bone marrow and liver. Sometimes, it may be the cause of prolonged pyrexia of unknown origin.2 The etiology of this disease is unknown, although several microorganisms, such as Epstein-Barr virus, human herpesviruses, toxoplasma and Yersinia enterocolitica have been implicated. However, the clinical, histopathological and immunohistochemical features favor a viral etiology, a hypothesis that is yet to be proven. Electron microscopic studies have identified tubular reticular structures in the cytoplasm of reactive lymphocytes and histiocytes in these patients.5 These structures have also been observed in endothelial cells and lymphocytes of patients with autoimmune disorders, it has been hypothesized that KFD may reflect a self-limited autoimmune condition induced by virus-infected transformed lymphocytes.6 KFD may signify a florid T-cell-mediated immune response in a genetically susceptible individual to nonspecific stimuli.7 It has been associated to systemic lupus erythematosus (SLE), mixed connective tissue disorders and leaking silicone breast implants.8 The recognition of KD is essential since it is a self-limiting disease and can be mistaken for various diseases such as SLE, malignant lymphoma, KD, tuberculosis or rarely metastatic deposit.2,9 Malignant lymphoma can mimic KD on hematoxylin and eosin (H&E) stained section and hence, careful examination and immunohistochemical work-up should be done to rule out lymphomas.

In case of metastasis of adenocarcinoma to lymph node, one should look for the presence of mucinproducing cells. KD exhibits geographic necrosis and neutrophilic infiltration. Infectious adenitis, especially with mycobacteria must be ruled out before the diagnosis of KD. Various laboratory investigations help to rule out other causes of lymphadenopathy associated

with fever. However, no such specific tests are available for detecting KD. Individuals affected with KD may show mild leukopenia with atypical lymphocytes in the peripheral blood, elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) or rarely, leukocytosis. The present case had leukopenia and reactive lymphocytes. Enzyme lactate dehydrogenase (LDH) level is generally increased, which suggests hepatic involvement.2 Studies to detect antinuclear antibody would further help in ruling out the autoimmune disease SLE. FNAC of KD show distinct features that may suggest the diagnosis such as good number of crescentic histiocytes, plasmacytoid monocytes, mixed population of lymphocytes and numerous karyorrhectic bodies.9 The cell types on FNAC varies based on the stage of disease. Crescentic histiocytes, plasmacytoid monocytes, atypical lymphocytes and karyorrhectic debris are seen in proliferative stage while eosinophilic necrosis, karyorrhectic debris, mixed population of lymphoid cells, abundant histiocytes and plasmacytoid monocytes occur in necrotizing stage. Scanty or no necrosis, karyorrhectic debris and foamy histiocytes feature in xanthomatous stage.9 However, the accuracy rate for the diagnose KD on FNAC is low and hence, the gold standard for the diagnosis of KFD is histomorphology of excised affected lymph nodes. Characteristic histopathologic findings include pale nodular foci composed of phagocytic and nonphagocytic histiocytes, small lymphocytes and immunoblasts interspersed with eosinophilic granular debris and basophilic karyorrhectic debris. Karyorrhectic debris is predominantly noted in the paracortical region. Zones of coagulative necrosis in cortical and paracortical areas and plasmacytoid monocytes are also noted. In the nonpathologic areas, there is prominent mottling by histiocytes or transformed lymphoid cells.

In spite of presence of nuclear debris and coagulative necrosis, the notable feature is the absence of neutrophilic infiltration. Apoptosis related changes in nucleus such as thickening of nuclear membrane, apoptotic bodies and finger-like network of apoptotic process have been noted on electron microscopy and hence the apoptotic

pathway would be responsible for the morphological changes occurring in the involved nodes.10 Treatment is symptomatic with analgesics-antipyretics, nonsteroidal anti-inflammatory drugs (NSAIDs) and, rarely, corticosteroids. Spontaneous recovery occurs in 1-4 months. Surgical treatment involves excision of nodes, in recurring disease.8 Conclusion To conclude, in addition to malignant lesions, KD should be considered in the differential diagnosis in older women with axillary lymphadenopathy.

References 1. Lee KY, Yeon YH, Lee BC. Kikuchi-Fujimoto disease with prolonged fever in children. Pediatrics 2004;114(6): e752-6.

2. Bosch X, Guilabert A. Kikuchi-Fujimoto disease. Orphanet J Rare Dis 2006;1:18.

3. Han HJ, Lim GY, Yeo DM, Chung NG. Kikuchi’s disease in children: clinical manifestations and imaging features.

J Korean Med Sci 2009;24(6):1105-9.

4. Tsang WY, Chan JK, Ng CS. Kikuchi’s lymphadenitis.

A morphologic analysis of 75 cases with special reference to unusual features. Am J Surg Pathol 1994;18(3):219-31.

5. Dorfman RF. Histiocytic necrotizing lymphadenitis of Kikuchi and Fujimoto. Arch Pathol Lab Med 1987;111(11):1026-9.

6. Imamura M, Ueno H, Matsuura A, Kamiya H, Suzuki T, Kikuchi K, et al. An ultrastructural study of subacute necrotizing lymphadenitis. Am J Pathol 1982;107(3): 292-9.

7. Bosch X, Guilabert A, Miquel R, Campo E. Enigmatic Kikuchi-Fujimoto disease: a comprehensive review. Am J Clin Pathol 2004;122(1):141-52.

8. Lin HC, Su CY, Huang CC, Hwang CF, Chien CY. Kikuchi’s disease: a review and analysis of 61 cases.

Otolaryngol Head Neck Surg 2003;128(5):650-3.

9. Hasan M, Zaheer S, Sofi LA, Parvez A. Fine-needle aspiration cytology of Kikuchi Fujimoto disease. J Cytol 2009;26(1):43-5.

10. Asano S, Akaike Y, Jinnouchi H, Muramatsu T, Wakasa H. Necrotizing lymphadenitis: a review of clinicopathological, immunohistochemical and ultrastructural studies. Hematol Oncol 1990;8(5):251-60.

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practice guidElines

photo quiz

ACP Releases Guideline on Intensive Insulin Therapy in Hospitalized Patients

Bubbles on the Skin Following Renal Transplant

H

yperglycemia is a common condition in medical and surgical patients during hospital admission, with a prevalence of approximately 40 percent. It is linked to poor immune response, increased cardiovascular events, and thrombosis, among other problems. Uncontrolled hyperglycemia is associated with increased morbidity, mortality, and costs. Achieving tight glycemic control in hospitalized patients often involves intensive insulin protocols.

Intensive insulin therapy is defined as the use of intravenous insulin to meet target blood glucose levels with frequent glucose testing and adjustment of insulin doses. In the intensive care unit (ICU) setting, the usual target range for blood glucose (normoglycemia) is 80 to 110 mg per dL (4.4 to 6.1 mmol per L). In non-ICU settings, target glucose levels vary, ranging from 80 to 110 mg per dL to less than 200 mg per dL (11.1 mmol per L).

The American College of Physicians (ACP) has issued a clinical guideline on the use of intensive insulin therapy in hospitalized patients with or without diabetes mellitus to achieve glycemic control and improve health outcomes. Most of the studies evaluated in the literature search focused on patients in the medical intensive care unit (MICU) and surgical intensive care unit (SICU).

Recommendation 1: Intensive insulin therapy should not be used to strictly control blood glucose in non-SICU/MICU patients with or without diabetes (strong recommendation; moderate-quality evidence). Available evidence showed no reduction in mortality with a target blood glucose level of 80 to 180 mg per dL (4.4 to 10.0 mmol per L) compared with a higher or unspecified target. Studies found in the literature review used a variety of intensive insulin therapy regimens in patients with myocardial infarction, stroke, or acute brain injury, or in patients under perioperative care. Harms were more likely to occur at lower target levels; therefore, target levels less than 140 mg per dL (7.8 mmol per L) should be avoided.

The effects of hypoglycemia in hospitalized patients are unclear, although there is some evidence for increased mortality or extended length of stay in patients who Source: Adapted from Am Fam Physician. 2011;84(9):1058-1060.

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have one or more episode of hypoglycemia. Some studies found that hypoglycemia is associated with an increased risk of dementia in patients with type 2 diabetes, and that hypoglycemia may induce transient ischemia and catecholamine surges. There is no optimal target blood glucose level in non-SICU/MICU patients because studies found that intensive insulin therapy was associated with an increased risk of hypoglycemia, with no differences in mortality at any specific target level.

Recommendation 2: Intensive insulin therapy should not be used to normalize blood glucose in SICU/MICU patients with or without diabetes (strong recommendation; highquality evidence). No mortality benefit was found using intensive insulin therapy to achieve normoglycemia.

Some studies showed an increase in mortality associated with intensive insulin therapy and hypoglycemia. Data were inconclusive on the association between intensive insulin therapy targeted to normoglycemia and the length of stay in the ICU. Recommendation 3: A target blood glucose level of 140 to 200 mg per dL (7.8 to 11.1 mmol per L) is recommended if insulin therapy is used in SICU/MICU patients (weak recommendation; moderate-quality evidence). Because poorly controlled hyperglycemia is associated with increased morbidity and mortality, and worse health outcomes in ICU patients, a target blood glucose level of 140 to 200 mg per dL is appropriate. Insulin therapy targeted to this range is associated with similar mortality outcomes and a lower risk of hypoglycemia compared with therapy targeted to 80 to 110 mg per dL. There is not enough evidence to determine whether blood glucose levels of 180 to 200 mg per dL (10.0 to 11.1 mmol per L) are associated with outcomes similar to those of lower target levels. Hypoglycemia was observed in studies using a range of target levels, although the risk was higher when lower target values were used. Achieving glucose targets with low rates of hypoglycemia may be associated with titration characteristics of the protocol, patient characteristics, staffing ratios, and physician acceptance. Quality improvement and training initiatives should be incorporated in hospitals to achieve target glucose levels while minimizing rates of hypoglycemia in ICU patients.

A

51-year-old man developed a mild fever and several serous vesicles on an erythematous base on his trunk (Figures 1 and 2) three months after having a renal transplant. During the following 10 days, similar lesions developed on his neck, upper arms, lower back, and inner thigh. The patient had the transplant because of end-stage renal disease related to interstitial nephritis. He had received a kidney from his father and was on immunosuppressive therapy.

Physical examination was otherwise normal, with no evidence of secondary infection. Complete blood count, liver enzyme level, and serum creatinine level were normal. A Tzanck test from a vesicle showed giant cells and acantholytic cells.

Figure 1.

Question Based on the patientâ&#x20AC;&#x2122;s history, physical examination, and laboratory results, which one of the following is the most likely diagnosis?

A. Cytomegalovirus.

B. Epstein-Barr virus.

C. Herpes simplex virus.

D. Herpes zoster.

E. Varicella-zoster virus.

Figure 2.

SEE THE FOLLOWING PAGE FOR DISCUSSION.

Source: Adapted from Am Fam Physician. 2011;84(9):1035-1036.

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medilaw

photo quiz Discussion

Summary Table

The answer is E: varicella-zoster virus infection.

Condition

Patients with a primary infection typically present with fever, constitutional symptoms, and a vesicular, pruritic, widely disseminated rash that primarily involves the trunk and face.1 In patients who have had an organ transplant, symptoms usually resolve without complication. In rare cases, however, primary varicella leads to more severe disease and visceral invasion.1 Complications of varicella can be life threatening and include hepatitis, pancreatitis, pneumonitis, and encephalitis.1 Definitive laboratory testing, including polymerase chain reaction assays, direct fluorescent antibody testing on skin scrappings, viral culture, and serology, can be used for atypical cases of varicella and should be used routinely for suspected disseminated or visceral disease.1,2 Test results positive for immunoglobulin G and immunoglobulin M indicate a recent infection with varicella-zoster virus. Patients who develop primary varicella, or disseminated or organ-invasive disease following a transplant should be treated with intravenous acyclovir.1-3 The cutaneous manifestations of cytomegalovirus infection in organ transplant recipients are nonspecific.

Cutaneous lesions may include ulcers, morbilliform rash, petechiae, purpuric eruptions, necrotic papules, and vesiculobullous eruptions.2 Epstein-Barr virus infection can cause a diffuse maculopapular and morbilliform rash. The lesions are vesicular, erythematous, and purpuric and may be accompanied by fever, pharyngitis, and lymphadenopathy.2 Organ transplant recipients with herpes simplex virus infection typically present with mucocutaneous lesions of the oropharynx. The herpetic vesicles break down to form shallow, grouped erosions and ulcers. In patients with immunosuppression, these ulcers may become large, confluent, chronic, granulating, and slow healing.1,2 Herpes zoster appears as a painful vesicular rash in a dermatomal distribution. Patients with herpes zoster who

Characteristics in organ transplant recipients

Cytomegalovirus Nonspecific cutaneous lesions; may include ulcers, morbilliform rash, petechiae, purpuric eruptions, necrotic papules, and vesiculobullous eruptions Epstein-Barr virus

Herpes simplex virus

Diffuse maculopapular, morbilliform rash with vesicular, erythematous, purpuric lesions; may be accompanied by fever, pharyngitis, and lymphadenopathy Mucocutaneous lesions of the oropharynx; vesicles form into shallow, grouped erosions and ulcers; patients with immunosuppression may have large confluent, chronic, granulating, slow-healing ulcers

Herpes zoster

Painful vesicular rash in a dermatomal distribution; patients with immunosuppression may have disseminated skin lesions mimicking varicella

Varicella-zoster virus

Typically a vesicular, pruritic, widely disseminated rash that usually involves the trunk and face and is accompanied by fever and constitutional symptoms; rarely, primary varicella leads to more severe disease and visceral invasion

are immunocompromised may develop disseminated skin lesions that can mimic primary varicella during periods of prominent immunosuppression. All patients with previous varicella infection or vaccination are at risk of herpes zoster.2

Registration of IVF Lab under PNDT Act MC Gupta

Q. The clinic of a doctor colleague of mine is registered as an ultrasound centre under the PNDT Act. He also has an IVF lab. The civil surgeon wants him to get his lab registered under the PNDT Act. Is there such a requirement?

2. Tan HH, Goh CL. Viral infections affecting the skin in organ transplant recipients. Am J Clin Dermatol.

2006;7(1):13-29.

ÂÂ

ÂÂ

For a centre to be registered under the PNDT Act, Form A has to be filled, which is titled—”Form of application for registration or renewal of registration of a genetic counselling centre/genetic laboratory/genetic clinic/ultrasound clinic/imaging centre” Your friend would do well to remember that the requirement for registration depends not on the name or title of the centre but upon what is done there. He needs to check whether his centre is covered by the definition of a “genetic counselling centre/genetic laboratory/genetic clinic” as defined in subsections (c), (d) and (e) of Section 2 of the Act, reproduced below: zz

“Genetic Counselling Centre” means an institute, hospital, nursing home or any place, by whatever name called, which provides for genetic counselling to patients;

zz

“Genetic Clinic” means a clinic, institute, hospital, nursing home or any place, by whatever name called, which is used for conducting pre-natal diagnostic procedures.

3. Sun HY, Singh N. Pharmacotherapy of post-transplant viral infections. Expert Opin Pharmacother. 2008;9(14): 2409-2421.

zz

“Genetic Laboratory” means a laboratory and includes a place where facilities are provided for conducting analysis or tests of samples

Indian Journal of Clinical Practice, Vol. 23, No. 3, 6, August November 2012 2012

Explanation– For the purposes of this clause, ‘Genetic Laboratory’ includes a place where ultrasound machine or imaging machine or scanner or other equipment capable of determining sex of the foetus or a portable equipment which has the potential for detection of sex during pregnancy or selection of sex before conception, is used.”

ÂÂ

Whether your friend’s “IVF lab” needs to be registered under the PNDT Act will depend upon what procedures or techniques are carried out in the lab.

ÂÂ

It would be useful to review the procedures described in subsections (i), (j) and (k) of Section 2 of the PNDT Act. These are reproduced below:

Explanation– For the purposes of this clause, ‘Genetic Clinic’ includes a vehicle, where ultrasound machine or imaging machine or scanner or other equipment capable of determining sex of the foetus or a portable equipment which has the potential for detection of sex during pregnancy or selection of sex before conception, is used.

Advocate and Medicolegal Consultant, New Delhi

352

Ans.

REFERENCES 1. Pergam SA, Limaye AP; AST Infectious Diseases Community of Practice. Varicella zoster virus (VZV) in solid organ transplant recipients. Am J Transplant.

2009;9(suppl 4):S108-S115.

received from Genetic Clinic for pre-natal diagnostic test.

ÂÂ

zz

“pre-natal diagnostic procedures” means all gynaecological or obstetrical or medical procedures such as ultrasonography, foetoscopy, taking or removing samples of amniotic fluid, chorionic villi, blood or any other tissue or fluid of a man, or of a woman for being sent to a Genetic Laboratory or Genetic Clinic for conducting any type of analysis or pre-natal diagnostic tests for selection of sex before or after conception;

zz

“pre-natal diagnostic techniques” includes all pre-natal diagnostic procedures and pre-natal diagnostic tests;

zz

“pre-natal diagnostic test” means ultrasonography or any test or analysis of amniotic fluid, chorionic villi, blood or any tissue or fluid of a pregnant woman or conceptus conducted to detect genetic or metabolic disorders or chromosomal abnormalities or congenital anomalies or haemoglobinopathies or sex-linked diseases;

It is for your friend to determine whether his lab is covered by any of the above definitions. If he is covered, he will need to be registered. If he is not covered, there is no question of registration.

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lighter reading

How big is one?

A kangaroo kept getting out of his enclosure at the zoo. Knowing that he could hop high, the zoo officials put up a 10-foot fence. He was out the next morning, just sauntering around the zoo. A 20-foot fence was put up. Again he got out.

As a man walked a desolate beach one cold, gray morning he began to see another figure, far in the distance. Slowly the two approached each other, and he could make out a local native who kept leaning down, picking something up and throwing it out into the water. Time and again he hurled things into the ocean.

As the distance between them continued to narrow, the man could see that the native was picking up starfish that had been washed upon the beach and, one at a time, was throwing them back into the water. Puzzled, the man approached the native and asked what he was doing. “I’m throwing these starfish back into the ocean. You see its low tide right now and all of these starfish have been washed up onto the shore. If I don’t throw them back into the sea, they’ll die up here from lack of oxygen.”

“But there must be thousands of starfish on this beach,” the man replied. “You can’t possibly get to all of them. There are just too many. And this same thing is probably happening on hundreds of beaches all up and down this coast. Can’t you see that you can’t possibly make a difference?”

The local native smiled, bent down and picked up another starfish, and as he threw it back into the sea he replied, “Made a difference to that one!”

Each of us is but one person: limited, burdened with our own cares and responsibilities. We may feel there is so much to be done, and we have so little to give.

We’re usually short of everything, especially time and money.

Laugh a While

An Inspirational Story

Lighter Side of Medicine

When the fence was 40 feet high, a camel in the next enclosure asked the kangaroo, “How high do you think they’ll go?”

The kangaroo said, “About a thousand feet, unless somebody locks the gate at night!”

Two elderly gentlemen from a retirement centre were sitting on a bench under a tree when one turns to the other and says: “Slim, I’m 83 years old now and I’m just full of aches and pains. I know you’re about my age. How do you feel?”

Slim says, “I feel just like a newborn baby.”

“Really? Like a newborn baby!?”

“Yep. No hair, no teeth, and I think I just wet my pants.”

Dr. Good & Dr. Bad Situation: A patient with fever and low TSH had ESR >100.

It’s TB

This is thyroiditis

©IJCP Academy

When we leave this shore, there will still be millions of starfish stranded on the beach. Maybe we can’t change the whole world, but there isn’t one of us who can’t help change one person’s whole world. One at a time.

We can make a difference.

Quotes

—Ms Ritu Sinha

354

“If we wait until our lives are free from sorrow or difficulty, then we wait forever. And miss the entire point.”

—Dirk Benedict

Indian Journal of Clinical Practice, Vol. 23, No. 6, November 2012

Lesson: Thyroiditis typically has very high ESR and

low TSH.

Dr KK Aggarwal

Information for Authors Manuscripts should be prepared in accordance with the ‘Uniform requirements for manuscripts submitted to biomedical journals’ compiled by the International Committee of Medical Journal Editors (Ann. Intern. Med. 1992;96: 766-767).

Indian Journal of Clinical Practice strongly disapproves of the submission of the same articles simultaneously to different journals for consideration as well as duplicate publication and will decline to accept fresh manuscripts submitted by authors who have done so.

The boxed checklist will help authors in preparing their manuscript according to our requirements. Improperly prepared manuscripts may be returned to the author without review. The checklist should accompany each manuscript.

Authors may provide on the checklist, the names and addresses of experts from Asia and from other parts of the World who, in the authors’ opinion, are best qualified to review the paper.

Covering letter –

–

–

The covering letter should explain if there is any deviation from the standard IMRAD format (Introduction, Methods, Results and Discussion) and should outline the importance of the paper.

Principal/Senior author must sign the covering letter indicating full responsibility for the paper submitted, preferably with signatures of all the authors.

Articles must be accompanied by a declaration by all authors stating that the article has not been published in any other Journal/Book. Authors should mentioned complete designation and departments, etc. on the manuscript.

Manuscript – Three complete sets of the manuscript should be submitted and preferably with a CD; typed double spaced throughout (including references, tables and legends to figures).

–

The manuscript should be arranged as follow: Covering letter, Checklist, Title page, Abstract, Keywords (for indexing, if required), Introduction, Methods, Results, Discussion, References, Tables, Legends to Figures and Figures.

–

All pages should be numbered consecutively beginning with the title page.

departments and institutions where the work was performed, name of the corresponding authors, acknowledgment of financial support and abbreviations used.

– The title should be of no more than 80 characters and should represent the major theme of the manuscript.

A subtitle can be added if necessary.

– A short title of not more than 50 characters (including inter-word spaces) for use as a running head should be included.

– The name, telephone and fax numbers, e-mail and postal addresses of the author to whom communications are to be sent should be typed in the lower right corner of the title page.

– A list of abbreviations used in the paper should be included. In general, the use of abbreviations is discouraged unless they are essential for improving the readability of the text.

Summary – The summary of not more than 200 words. It must convey the essential features of the paper.

– It should not contain abbreviations, footnotes or references.

Introduction – The introduction should state why the study was carried out and what were its specific aims/objectives.

Methods – These should be described in sufficient detail to permit evaluation and duplication of the work by others.

– Ethical guidelines followed by the investigations should be described.

Statistics The following information should be given: – The statistical universe i.e., the population from which the sample for the study is selected.

– Method of selecting the sample (cases, subjects, etc. from the statistical universe).

– Method of allocating the subjects into different groups.

– Statistical methods used for presentation and analysis of data i.e., in terms of mean and standard deviation values or percentages and statistical tests such as Student’s ‘t’ test, Chi-square test and analysis of variance or non-parametric tests and multivariate techniques.

Note: Please keep a copy of your manuscript as we are not responsible for its loss in the mail. Manuscripts will not be returned to authors.

–

Confidence intervals for the measurements should be provided wherever appropriate.

Title page Should contain the title, short title, names of all the authors (without degrees or diplomas), names and full location of the

– These should be concise and include only the tables and figures necessary to enhance the understanding of the text.

Results

Indian Journal of Clinical Practice, Vol. 23, No. 6, November 2012

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Discussion –

This should consist of a review of the literature and relate the major findings of the article to other publications on the subject. The particular relevance of the results to healthcare in India should be stressed, e.g., practicality and cost.

References These should conform to the Vancouver style. References should be numbered in the order in which they appear in the texts and these numbers should be inserted above the lines on each occasion the author is cited (Sinha12 confirmed other reports13,14...). References cited only in tables or in legends to figures should be numbered in the text of the particular table or illustration. Include among the references papers accepted but not yet published; designate the journal and add ‘in press’ (in parentheses). Information from manuscripts submitted but not yet accepted should be cited in the text as ‘unpublished observations’ (in parentheses).

At the end of the article the full list of references should include the names of all authors if there are fewer than seven or if there are more, the first six followed by et al., the full title of the journal article or book chapters; the title of journals abbreviated according to the style of the Index Medicus and the first and final page numbers of the article or chapter. The authors should check that the references are accurate. If they are not this may result in the rejection of an otherwise adequate contribution.

Examples of common forms of references are: Articles Paintal AS. Impulses in vagal afferent fibres from specific pulmonary deflation receptors. The response of those receptors to phenylguanide, potato S-hydroxytryptamine and their role in respiratory and cardiovascular reflexes.

Q. J. Expt. Physiol. 1955;40:89-111.

Figures – Two complete sets of glossy prints of high quality should be submitted. The labelling must be clear and neat.

– All photomicrographs should indicate the magnification of the print.

– Special features should be indicated by arrows or letters which contrast with the background.

– The back of each illustration should bear the first author’s last name, figure number and an arrow indicating the top. This should be written lightly in pencil only. Please do not use a hard pencil, ball point or felt pen.

– Color illustrations will be accepted if they make a contribution to the understanding of the article.

–

Do not use clips/staples on photographs and artwork.

–

Illustrations must be drawn neatly by an artist and photographs must be sent on glossy paper. No captions should be written directly on the photographs or illustration. Legends to all photographs and illustrations should be typed on a separate sheet of paper. All illustrations and figures must be referred to in the text and abbreviated as “Fig.”.

Please complete the following checklist and attach to the manuscript: 1. Classification (e.g. original article, review, selected summary, etc.)_______________________________ 2. Total number of pages ________________________ 3. Number of tables ____________________________ 4. Number of figures ___________________________

Books

5. Special requests _____________________________

Stansfield AG. Lymph Node Biopsy Interpretation Churchill Livingstone, New York 1985.

Indian 1.____________Foreign 1.________________

Articles in Books

2.____________ 2.________________

Strong MS. Recurrent respiratory papillomatosis. In: Scott Brown’s Otolaryngology. Paediatric Otolaryngology Evans JNG (Ed.), Butterworths, London 1987;6:466-470.

3.____________ 3.________________

4.____________ 4.________________

Tables –

These should be typed double spaced on separate sheets with the table number (in Roman Arabic numerals) and title above the table and explanatory notes below the table.

Legends – These should be typed double spaces on a separate sheet and figure numbers (in Arabic numerals) corresponding with the order in which the figures are presented in the text.

–

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The legend must include enough information to permit interpretation of the figure without reference to the text.

Indian Journal of Clinical Practice, Vol. 23, No. 6, November 2012

6. Suggestions for reviewers (name and postal address)

7. All authors’ signatures________________________ 8.

Corresponding author’s name, current postal and e-mail address and telephone and fax numbers __________________________________________

Online Submission Also e- Issue @ www.ijcpgroup.com For Editorial Correspondence

Dr KK Aggarwal Group Editor-in-Chief Indian Journal of Clinical Practice E-219, Greater Kailash, Part-1 New Delhi - 110 048. Tel: 40587513 E-mail: editorial@ijcp.com Website: www.ijcpgroup.com

R.N.I. No. 50798/90 Date of Publication 13th of Same Month Date of Posting 13-14 Same Month

DL (S)-01/3200/2012-2014 Posted in N.D. PSO New Delhi