Shabir Lakhi

Effect of an Early Resuscitation Protocol on In-hospital Mortality Among Adults With Sepsis and Hypotension: A Randomized Clinical Trial

Importance The effect of an early resuscitation protocol on sepsis outcomes in developing countries remains unknown. Objective To determine whether an early resuscitation protocol with administration of intravenous fluids, vasopressors, and blood transfusion decreases mortality among Zambian adults with sepsis and hypotension compared with usual care. Design, Setting, and Participants Randomized clinical trial of 212 adults with sepsis (suspected infection plus ≥2 systemic inflammatory response syndrome criteria) and hypotension (systolic blood pressure ⩽90 mm Hg or mean arterial pressure ⩽65 mm Hg) presenting to the emergency department at a 1500-bed referral hospital in Zambia between October 22, 2012, and November 11, 2013. Data collection concluded December 9, 2013. Interventions Patients were randomized 1:1 to either (1) an early resuscitation protocol for sepsis (n = 107) that included intravenous fluid bolus administration with monitoring of jugular venous pressure, respiratory rate, and arterial oxygen saturation and treatment with vasopressors targeting mean arterial pressure (≥65 mm Hg) and blood transfusion (for patients with a hemoglobin level <7 g/dL) or (2) usual care (n = 105) in which treating clinicians determined hemodynamic management. Main Outcomes and Measures The primary outcome was in-hospital mortality and the secondary outcomes included the volume of intravenous fluid received and receipt of vasopressors. Results Among 212 patients randomized to receive either the sepsis protocol or usual care, 3 were ineligible and the remaining 209 completed the study and were included in the analysis (mean [SD] age, 36.7 [12.4] years; 117 men [56.0%]; 187 [89.5%] positive for the human immunodeficiency virus). The primary outcome of in-hospital mortality occurred in 51 of 106 patients (48.1%) in the sepsis protocol group compared with 34 of 103 patients (33.0%) in the usual care group (between-group difference, 15.1% [95% CI, 2.0%-28.3%]; relative risk, 1.46 [95% CI, 1.04-2.05]; P = .03). In the 6 hours after presentation to the emergency department, patients in the sepsis protocol group received a median of 3.5 L (interquartile range, 2.7-4.0 L) of intravenous fluid compared with 2.0 L (interquartile range, 1.0-2.5 L) in the usual care group (mean difference, 1.2 L [95% CI, 1.0-1.5 L]; P < .001). Fifteen patients (14.2%) in the sepsis protocol group and 2 patients (1.9%) in the usual care group received vasopressors (between-group difference, 12.3% [95% CI, 5.1%-19.4%]; P < .001). Conclusions and Relevance Among adults with sepsis and hypotension, most of whom were positive for HIV, in a resource-limited setting, a protocol for early resuscitation with administration of intravenous fluids and vasopressors increased in-hospital mortality compared with usual care. Further studies are needed to understand the effects of administration of intravenous fluid boluses and vasopressors in patients with sepsis across different low- and middle-income clinical settings and patient populations. Trial Registration clinicaltrials.gov Identifier: NCT01663701

HIV, Hepatitis B, and Hepatitis C in Zambia.

Objectives Epidemiologic data of HIV and viral hepatitis coinfection are needed in sub-Saharan Africa to guide health policy for hepatitis screening and optimized antiretroviral therapy (ART). Materials and Methods: We screened 323 HIV-infected, ART-eligible adults for hepatitis B surface antigen (HBsAg) and hepatitis C antibody (HCV Ab) at a tertiary hospital in Lusaka, Zambia. We collected basic demographic, medical, and laboratory data to determine predictors for coinfection. Results: Of 323 enrolled patients, 32 (9.9%; 95% CI=6.7–13.2%) were HBsAg positive, while 4 (1.2%; 95% CI=0.03–2.4%) were HCV Ab positive. Patients with hepatitis B coinfection were more likely to be <40 years (84.4% vs. 61.4%; P=0.01) when compared to those who were not coinfected. Patients with active hepatitis B were more likely to have mild to moderately elevated AST/ALT (40–199 IU/L, 15.8% vs. 5.4%; P=0.003). Highly elevated liver enzymes (>200 IU/L) was uncommon and did not differ between the two groups (3.4% vs. 2.3%; P=0.5). We were unable to determine predictors of hepatitis C infection due to the low prevalence of disease. Conclusions: HIV and hepatitis B coinfection was common among patients initiating ART at this tertiary care facility. Routine screening for hepatitis B should be considered for HIV-infected persons in southern Africa.

Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa

BACKGROUND Cryptococcal meningitis accounts for more than 100,000 human immunodeficiency virus (HIV)–related deaths per year. We tested two treatment strategies that could be more sustainable in Africa than the standard of 2 weeks of amphotericin B plus flucytosine and more effective than the widely used fluconazole monotherapy. METHODS We randomly assigned HIV‐infected adults with cryptococcal meningitis to receive an oral regimen (fluconazole [1200 mg per day] plus flucytosine [100 mg per kilogram of body weight per day] for 2 weeks), 1 week of amphotericin B (1 mg per kilogram per day), or 2 weeks of amphotericin B (1 mg per kilogram per day). Each patient assigned to receive amphotericin B was also randomly assigned to receive fluconazole or flucytosine as a partner drug. After induction treatment, all the patients received fluconazole consolidation therapy and were followed to 10 weeks. RESULTS A total of 721 patients underwent randomization. Mortality in the oral‐regimen, 1‐week amphotericin B, and 2‐week amphotericin B groups was 18.2% (41 of 225), 21.9% (49 of 224), and 21.4% (49 of 229), respectively, at 2 weeks and was 35.1% (79 of 225), 36.2% (81 of 224), and 39.7% (91 of 229), respectively, at 10 weeks. The upper limit of the one‐sided 97.5% confidence interval for the difference in 2‐week mortality was 4.2 percentage points for the oral‐regimen group versus the 2‐week amphotericin B groups and 8.1 percentage points for the 1‐week amphotericin B groups versus the 2‐week amphotericin B groups, both of which were below the predefined 10‐percentage‐point noninferiority margin. As a partner drug with amphotericin B, flucytosine was superior to fluconazole (71 deaths [31.1%] vs. 101 deaths [45.0%]; hazard ratio for death at 10 weeks, 0.62; 95% confidence interval [CI], 0.45 to 0.84; P=0.002). One week of amphotericin B plus flucytosine was associated with the lowest 10‐week mortality (24.2%; 95% CI, 16.2 to 32.1). Side effects, such as severe anemia, were more frequent with 2 weeks than with 1 week of amphotericin B or with the oral regimen. CONCLUSIONS One week of amphotericin B plus flucytosine and 2 weeks of fluconazole plus flucytosine were effective as induction therapy for cryptococcal meningitis in resource‐limited settings. (ACTA Current Controlled Trials number, ISRCTN45035509.)

Genomic epidemiology of Cryptococcus yeasts identifies adaptation to environmental niches underpinning infection across an African HIV/AIDS cohort.

Emerging infections caused by fungi have become a widely recognized global phenomenon and are causing an increasing burden of disease. Genomic techniques are providing new insights into the structure of fungal populations, revealing hitherto undescribed fine‐scale adaptations to environments and hosts that govern their emergence as infections. Cryptococcal meningitis is a neglected tropical disease that is responsible for a large proportion of AIDS‐related deaths across Africa; however, the ecological determinants that underlie a patients risk of infection remain largely unexplored. Here, we use genome sequencing and ecological genomics to decipher the evolutionary ecology of the aetiological agents of cryptococcal meningitis, Cryptococcus neoformans and Cryptococcus gattii, across the central African country of Zambia. We show that the occurrence of these two pathogens is differentially associated with biotic (macroecological) and abiotic (physical) factors across two key African ecoregions, Central Miombo woodlands and Zambezi Mopane woodlands. We show that speciation of Cryptococcus has resulted in adaptation to occupy different ecological niches, with C. neoformans found to occupy Zambezi Mopane woodlands and C. gattii primarily recovered from Central Miombo woodlands. Genome sequencing shows that C. neoformans causes 95% of human infections in this region, of which over three‐quarters belonged to the globalized lineage VNI. We show that VNI infections are largely associated with urbanized populations in Zambia. Conversely, the majority of C. neoformans isolates recovered in the environment belong to the genetically diverse African‐endemic lineage VNB, and we show hitherto unmapped levels of genomic diversity within this lineage. Our results reveal the complex evolutionary ecology that underpins the reservoirs of infection for this, and likely other, deadly pathogenic fungi.

Association of the APOE, MTHFR and ACE Genes Polymorphisms and Stroke in Zambian Patients.

The aim of the present study was to investigate the association of APOE, MTHFR and ACE polymorphisms with stroke in the Zambian population. We analyzed 41 stroke patients and 116 control subjects all of Zambian origin for associations between the genotype of the APOE, MTHFR and ACE polymorphisms and stroke. The APOE ε2ε4 genotype showed increased risk for hemorrhagic stroke (P<0.05) and also a high risk for ischemic stroke (P=0.05). There was complete absence of the APOE ε2ε2 and the MTHFR TT genotypes in the Zambian population. The difference between cases and controls was not significant for the other genetic variants when analyzed for relationship between stroke, stroke subtype and genotype. We show that genetic variation at the APOE locus affects susceptibility to stroke. No detectable association were observed for the MTHFR and ACE genotypes and stroke in the Zambian population.

Stroke Characteristics and Outcomes of Adult Patients Admitted to theUniversity Teaching Hospital, Lusaka, Zambia

Objectives: Despite the high burden of strokes globally and among people of African origin in particular, there are few available data on stroke in most countries of sub-Saharan Africa (SSA), including Zambia. The aim of this study was to describe the characteristics and outcomes of stroke in adult Zambian patients admitted to the University Teaching Hospital (UTH) in Lusaka. Methods: The study was conducted at the UTH, which is the only tertiary hospital in the country, from July to December 2010. Stroke was confirmed by neurological examination and CT scan of the brain. Participants were assessed for risk factors and severity of stroke. Outcome measures included in-hospital stroke mortality and disability (modified Rankin score and Glasgow outcome scale on discharge). Results: A total of 250 consecutive stroke patients were included in the study. Of these 162 (65%) patients had ischemic and 88 (35%) hemorrhagic strokes. The mean age was 55 ±18years. Hypertension was most common risk factor for both strokes. Other risk factors included: alcohol intake (32.6%), previous stroke (23.6%), family history of stroke (23.2%), HIV infection (25.4%), hypercholesterolemia (14%) andtobacco smoking/sniffing (13.4%). In-hospital stroke mortality was 40%. Factors independently associated with mortality were female sex, pneumonia, Glasgow Coma Scale (GCS) � 8 and stroke severity at admission. Conclusions: Stroke in Zambian patients occurs at a relatively young age and frequency of intracerebral hemorrhage is higher than that reported in developed countries. Hypertension is common risk factor for both types of strokes. Family history of stroke is one of important risk factor. In-hospital stroke mortality is high at UTH. HIV infection is independently associated with ischemic stroke.

Developing a Successful Global Neurology Program

In the last decade, the field of global neurology has gained prominence. The American Academy of Neurology formed a global health section that currently has over 300 members. Numerous academic departments now have global neurology programs that provide support to institutions in lowand middle-income countries (LMICs). These relationships often take the form of patient care, teaching activities, research projects, and resident electives. The regulations surrounding clinical electives overseas are also clearer. Residency applicants often ask program directors about global neurology opportunities when interviewing, suggesting that residency programs that lack appropriate opportunities will become less competitive. A well-developed global neurology program provides a dynamic element for a department while enhancing neurological activities at both institutions involved in the collaboration.