Syed Asad Ali

Pathogens associated with sepsis in newborns and young infants in developing countries.

Introduction: Knowledge of pathogens causing infections in young infants (up to 90 days of life) is essential for devising community-based management strategies. Most etiological data from developing countries are hospital-based and may have little relevance to communities in which most babies are born at home. Methods: We searched the literature for studies from developing countries reporting etiology of community-acquired infections (sepsis, pneumonia, meningitis) published since 1980. Hospital-based studies reporting early onset sepsis, sepsis among babies admitted from, or born at home were included. Results: Of 63 studies, 13 focused on community-acquired infections, but limited data were available from home-born neonates. In the first week of life (3209 isolates), Klebsiella species (25%), Escherichia coli (15%), and Staphylococcus aureus (18%) were major pathogens. Group B streptococci (GBS) were relatively uncommon (7%), although regional differences existed. After the first week of life (835 isolates), S. aureus (14%), GBS (12%), Streptococcus pneumoniae (12%), and nontyphoidal Salmonella species (13%) were most frequent. S. pneumoniae (27%) was most common in the postneonatal period (among 141 isolates). Gram-negatives predominated (77%) among home-delivered babies (among 170 isolates). Conclusions: Limited information is available on etiology of serious bacterial infections in community settings. Hospital-based studies suggest that most infections in the first week of life are due to Gram-negative pathogens, and many may be environmentally rather than maternally-acquired, owing to unhygienic delivery practices. Such practices may also explain the predominance of Gram-negative infections among home-born infants, although data from home settings are limited. These findings have implications for developing prevention and management strategies in communities and hospitals.

Antimicrobial resistance among neonatal pathogens in developing countries.

Introduction: Knowledge of antimicrobial resistance and trends in resistance patterns among major pathogens causing infections in young infants (up to 90 days of life) is an important component of developing community-based management strategies. Hospital-based data suggest alarming rates of resistance to ampicillin and gentamicin, the first-line antimicrobial agents recommended by WHO for treatment of serious infections in young infants. Methods: We searched the literature published since 1990 for studies from developing countries reporting resistance among serious community-acquired infections (including sepsis, pneumonia, and meningitis) in young infants. Results: Only 10 relevant reports were retrieved. Among the 3 major pathogens studied (Escherichia coli, Staphyloccoccus aureus, and Klebsiella species), a high proportion of E. coli were ampicillin (72%) and cotrimoxazole (78%) resistant; 19% were resistant to third generation cephalosporins. Among Klebsiella species, almost all were resistant to ampicillin, 45% to cotrimoxazole, and 66% to third generation cephalosporins. Resistance to gentamicin was low among E. coli (13%), but much higher among Klebsiella species (60%). Methicillin resistance S. aureus (MRSA) was rare (1 of 33 isolates) but 46% were resistant to cotrimoxazole. Conclusions: Antimicrobial resistance data for infections in young infants from community-based studies were extremely limited. Significant resistance, in particular to cotrimoxazole among all pathogens, and to gentamicin and third generation cephalosporins among Klebsiella and emerging resistance in E. coli is cause for concern. Limited data pose a challenge in devising simple community-based management strategies. Further studies from different developing country regions are needed to determine prevalence of resistant strains, as well as assess regional and time trends.

Impact of Different Dosing Schedules on the Immunogenicity of the Human Rotavirus Vaccine in Infants in Pakistan - a Randomized Trial

BACKGROUND Current oral rotavirus vaccines perform suboptimally in resource-poor settings. We investigated the effect of an additional dose and later schedule on the immunogenicity of monovalent rotavirus vaccine (RV1) in a developing country. METHODS Infants received RV1 at 6 and 10, 10 and 14, or 6, 10, and 14 weeks of age. The primary objective was to compare antirotavirus immunoglobulin A (IgA) seroconversion at 18 weeks in the 6/10/14 arm to the cumulative seroconversion (highest result at 14 or 18 weeks) in the 6/10 arm. RESULTS Overall, 480 (76.2%) of 630 randomized infants completed the trial per protocol. Seroconversion in the 6/10/14 arm was 36.7% (95% CI, 29.8, 44.2) compared to 36.1% (CI, 29.0, 43.9) in the 6/10 arm, (P=1.0); the result from the 10/14 arm was 38.5% (CI, 31.2, 46.3). Seroconversion in the 6/10 arm at 14 weeks (post hoc) was lower at 29.7% (CI, 23.1, 37.3). CONCLUSIONS In Pakistani infants, the immunogenicity of RV1 did not increase significantly with 3 doses at 6, 10, and 14 weeks compared to 2 doses at 6 and 10 weeks. Additional strategies should be evaluated for improving rotavirus vaccine immunogenicity in high burden countries.

Pakistan's expanded programme on immunization: An overview in the context of polio eradication and strategies for improving coverage

Since its inception in 1978, Pakistans Expanded Programme on Immunization (EPI) has contributed significantly towards child health and survival in Pakistan. However, the WHO-estimated immunization coverage of 88% for 3 doses of Diptheria-Tetanus-Pertussis vaccine in Pakistan is likely an over-estimate. Many goals, such as polio, measles and neonatal tetanus elimination have not been met. Pakistan reported more cases of poliomyelits in 2011 than any other country globally, threatening the Global Polio Eradication Initiative. Although the number of polio cases decreased to 58 in 2012 through better organized supplementary immunization campaigns, country-wide measles outbreaks with over 15,000 cases and several hundred deaths in 2012-13 underscore sub-optimal EPI performance in delivering routine immunizations. There are striking inequities in immunization coverage between different parts of the country. Barriers to universal immunization coverage include programmatic dysfunction at lower tiers of the program, socioeconomic inequities in access to services, low population demand, poor security, and social resistance to vaccines among population sub-groups. Recent conflicts and large-scale natural disasters have severely stressed the already constrained resources of the national EPI. Immunization programs remain low priority for provincial and many district governments in the country. The recent decision to devolve the national health ministry to the provinces has had immediate adverse consequences. Mitigation strategies aimed at rapidly improving routine immunization coverage should include improving the infrastructure and management capacity for vaccine delivery at district levels and increasing the demand for vaccines at the population level. Accurate vaccine coverage estimates at district/sub-district level and local accountability of district government officials are critical to improving performance and eradicating polio in Pakistan.

Promising Biomarkers of Environmental Enteric Dysfunction: A Prospective Cohort study in Pakistani Children

Environmental Enteric Dysfunction (EED), a syndrome characterized by chronic gut inflammation, contributes towards stunting and poor response to enteric vaccines in children in developing countries. In this study, we evaluated major putative biomarkers of EED using growth faltering as its clinical proxy. Newborns (n = 380) were enrolled and followed till 18 months with monthly anthropometry. Biomarkers associated with gut and systemic inflammation were assessed at 6 and 9 months. Linear mixed effects model was used to determine the associations of these biomarkers with growth faltering between birth and 18 months. Fecal myeloperoxidase (neutrophil activation marker) at 6 months [β = −0.207, p = 0.005], and serum GLP 2 (enterocyte proliferation marker) at 6 and 9 months [6M: β = −0.271, p = 0.035; 9M: β = −0.267, p = 0.045] were associated with decreasing LAZ score. Ferritin at 6 and 9 months was associated with decreasing LAZ score [6M: β = −0.882, p < 0.0001; 9M: β = −0.714, p < 0.0001] and so was CRP [β = −0.451, p = 0.039] and AGP [β = −0.443, p = 0.012] at 9 months. Both gut specific and systemic biomarkers correlated negatively with IGF-1, but only weakly correlated, if at all with each other. We therefore conclude that EED may be contributing directly towards growth faltering, and this pathway is not entirely through the pathway of systemic inflammation.

Recurrent Salmonellosis in a Child with Complete IL-12Rβ1 Deficiency.

A 3 year old boy presented with fever, abdominal pain and cervical lymphadenopathy. He had previously been treated empirically with anti-tuberculous therapy twice, at age 9 months and 27 months, for peripheral lymphadenopathy. An older sibling died of suspected tuberculous meningitis. Mantoux test was normal. Bone marrow and lymph node biopsy ruled out lymphoma and absolute neutrophil and lymphocyte counts were normal. Blood and lymph node cultures were positive for Salmonella typhi. The childs symptoms resolved with IV ceftriaxone and he was discharged. Over the next 2 years, the child was admitted every 2-3 months for culture positive S. typhi bacteremia with complaints of fever, abdominal distention and dysentery. HIV workup was negative. A prolonged course of probenicid and high dose amoxicillin increased interval between episodes to 4-5 months only. Cholecystectomy was debated and deferred due to suspicion of immunodeficiency. Blood samples from patient and parents were sent to France for workup and IL-12Rβ1 deficiency was found. Parental counseling and subsequent patient management remained difficult in view of financial constraints and outstation residence of family. At age 7 years, the child presented with small bowel obstruction. He was managed conservatively with antibiotics, IV fluids and blood transfusions, but eventually succumbed to endotoxic shock. This case highlights the importance of considering IL-12Rβ1 deficiency in children with repeated salmonellosis, a diagnosis which precludes intensive and aggressive monitoring and management of the patient in scenarios where bone marrow transplants are not feasible.

Evaluation of antibiotic use in Pediatric Intensive Care Unit of a developing country

Background: Pediatric Intensive Care Unit (PICU) patients are often prescribed antibiotics with a low threshold in comparison to patients elsewhere. Irrational antibiotics use can lead to rapid emergence of drug resistance, so surveillance of their use is important. Objectives: To evaluate the use of antibiotics in relation to bacteriological findings in PICU of a Tertiary Hospital. Methods: Retrospective review of medical records of all children (age 1 month–16 years) admitted in our closed multidisciplinary-cardiothoracic PICU from January to June 2013 was performed, after approval from Ethical Review Committee. For each antibiotic, indication (prophylactic, empiric, therapeutic) and duration of use were recorded. All diagnoses of infections were recorded according to diagnostic criteria of IPSCC 2005. Results are presented as frequency and percentages and median with inter quartile range using SPSS version 19. Results: All of the total 240 patients admitted in PICU during the study period received antibiotics: 43% (n = 104) prophylactically, 42% (n = 102) empirically, and 15% (n = 15) therapeutically. Median number of antibiotic use per patient in PICU was 3, with range of 1–7. 25% received 1 antibiotic, 23% received 2 antibiotics, 29% received 3 antibiotics, and rest received ≥4 antibiotics. Most commonly used antibiotics were cefazolin, meropenem, vancomycin and ceftriaxone, and most frequently used combination was meropenem and vancomycin. In majority of the cases, (70%) empiric antibiotic combinations were stopped in 72 h. Conclusion: This is the first report of antibiotics use in PICU from our country, which shows that antibiotics are prescribed universally in our PICU. Strategies to assess the need for antibiotic use are needed.

Pandemic influenza A(H1N1)pdm09: An unrecognized cause of mortality in children in Pakistan

Abstract The role of influenza virus as a cause of child mortality in South Asia is under-recognized. We aimed to determine the incidence and case fatality rate of influenza A(H1N1)pdm09 infections in hospitalized children in Karachi, Pakistan. Children less than 5 y old admitted with respiratory illnesses to the Aga Khan University Hospital, Karachi, from 17 August 2009 to 16 September 2011, were tested for influenza A(H1N1)pdm09 using a real-time reverse transcriptase polymerase chain reaction. Out of 2650 children less than 5 y old admitted with a respiratory illness during the study period, 812 (31%) were enrolled. Influenza A(H1N1)pdm09 virus was detected in 27 (3.3%) children. There were 4 deaths in children who tested positive for influenza A(H1N1)pdm09 (case fatality rate of 15%). Children with influenza A(H1N1)pdm09 were 5 times more likely to be admitted or transferred to the intensive care unit, 5.5 times more likely to be intubated, and 12.9 times more likely to die as compared to children testing negative for influenza A(H1N1)pdm09.

Effect of Mobile Phone Text Message Reminders on Routine Immunization Uptake in Pakistan: Randomized Controlled Trial

Background Improved routine immunization (RI) coverage is recommended as the priority public health strategy to decrease vaccine-preventable diseases and eradicate polio in Pakistan and worldwide. Objective The objective of this study was to ascertain whether customized, automated, one-way text messaging (short message service, SMS) reminders delivered to caregivers via mobile phones when a child is due for an RI visit can improve vaccination uptake and timelines in Pakistan. Methods This was a randomized controlled trial, conducted in an urban squatter settlement area of Karachi, Pakistan. Infants less than 2 weeks of age with at least one family member who had a valid mobile phone connection and was comfortable receiving and reading SMS text messages were included. Participants were randomized to the intervention (standard care + one-way SMS reminder) or control (standard care) groups. The primary outcome was to compare the proportion of children immunized up to date at 18 weeks of age. Vaccine given at 6, 10, and 14 weeks schedule includes DPT-Hep-B-Hib vaccine (ie, diphtheria, pertussis, and tetanus; hepatitis B; and Haemophilus influenza type b) and oral poliovirus vaccine (OPV). Data were analyzed using chi-square tests of independence and tested for both per protocol (PP) and intention-to-treat (ITT) analyses. Results Out of those approached, 84.3% (300/356) of the participants were eligible for enrollment and 94.1% (318/338) of the participants had a working mobile phone. Only children in the PP analyses, who received an SMS reminder for vaccine uptake at 6 weeks visit, showed a statistically significant difference (96.0%, 86/90 vs 86.4%, 102/118; P=.03).The immunization coverage was consistently higher in the intervention group according to ITT analyses at the 6 weeks scheduled visit (76.0% vs 71.3%, P=.36). The 10 weeks scheduled visit (58.7% vs 52.7%, P=.30) and the 14 weeks scheduled visit (31.3% vs 26.0%, P=.31), however, were not statistically significant. Conclusions Automated simple one-way SMS reminders in local languages might be feasible for improving routine vaccination coverage. Whether one-way SMS reminders alone can have a strong impact on parental attitudes and behavior for improvement of RI coverage and timeliness needs to be further evaluated by better-powered studies and by comparing different types and content of text messages in low-and middle-income countries (LMICs). Trial Registration ClinicalTrials.gov NCT01859546; https://clinicaltrials.gov/ct2/show/NCT01859546 (Archived by WebCite at http://www.webcitation.org/6xFr57AOc)

Knowledge, attitudes and practices related to tetanus toxoid vaccination in women of childbearing age: A cross-sectional study in peri-urban settlements of Karachi, Pakistan:

Backgound: A higher incidence of neonatal tetanus implies failure of the vaccination program in Pakistan. Objectives: The objective of this study was to assess knowledge, attitudes and practices related to tetanus toxoid (TT) vaccine in women of childbearing age. Methods: We performed a cross-sectional survey in peri-urban Karachi, Pakistan, among women of childbearing age, stratified into three mutually exclusive groups as: married pregnant; married non-pregnant; and unmarried. Descriptive and inferential analyses were performed to estimate vaccine coverage and knowledge attributes. Results: A total of 450 women participated, of which the largest proportion were married and non-pregnant (n = 185/450, 41%). Over 50% of women (n = 258/450) had not received TT vaccine. Most unmarried women (n = 139, 97%) were unvaccinated. Non-vaccination predictors included: women aged <25 years without any formal education (adjusted odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.4), lack of knowledge about free vaccination (adjusted OR, 4.0; 95% CI, 1.64–10.20), poor knowledge of tetanus disease/vaccination (adjusted OR, 4.6; 95%, 2.2–9.6), living with extended family (adjusted OR, 2.0; 95% CI, 1.04–3.96); family non-supporting vaccination (adjusted OR, 5.7; 95% CI, 2.3–13.9); and husband/other family member deciding upon issues related to women’s health (adjusted OR, 2.9; 95% CI, 1.3–6.6). Conclusion: Low coverage of TT vaccine is largely influenced by poor knowledge, family structure and family decision-making in the local communities of Pakistan.