Pakistan floods: Incidence of vector- and water-borne infectious diseases soars

Another year bears witness to a novel humanitarian disaster that is linked to extreme weather events seemingly associated with climate change. This time it is in Pakistan, the South Asian nation of 220 million people. Record-breaking monsoonal rains started in mid-June 2022, which have been attributed to a La Niña oceanic and atmospheric phenomenon. This compounded the glacial melts of April and May in the northern Gilgit-Baltistan and Khyber Pakhtunkhwa regions that had caused an already swollen Indus river system that runs the length of the country. More than 33 million residents have been affected by the ensuing devastating floods that hit the south-eastern province of Sindh. There, the rainfall in August was 726% higher than the average since records began in 1961. The neighboring south-western Baluchistan province is also extensively affected. Satellite images show that around one-third of Pakistan is underwater. From late August 2022, Pakistan’s public health system has been creaking under the enormous burden of clinical cases that has arisen. The suddenness and severity of the emergency has highlighted the national authority’s inadequate disaster planning and first responder mobilization

The Ly-4+ T Lymphocyte Subset in the Host Immune Response to the Asexual Stages of Plasmodium chabaudi chabaudi

T cells play a major role in acquired immunity to the asexual erythrocytic stages of malaria parasites. In different host/parasite combinations there is evidence that human CD4+ lymphocytes or their murine equivalent, Ly-4+, can act as helper cells in the production of protective Ab and also mediate cellular protective functions. The details of how the effector mechanisms operate in vivo, however, are not understood clearly. There is indirect evidence supporting an important role for Ly-4-bearing lymphocytes in the protective immune response to Plasmodium chabaudi chabaudi AS strain, a good animal model of P. falciparum infection. Experiments were performed to examine the nature of the Ly-4+ response to this parasite both in vivo and in vitro in order to characterise the cells responsible for the mediation of protective activity. Initial studies showed that during the course of a primary infection of P. c. chabaudi AS, there was a marked transient lymphocytosis in the peripheral blood, which occurred at a time just after peak parasitaemia (d 12-13 p. i. ). The adoptive transfer to syngeneic NIH recipients of either peripheral blood or splenic lymphocytes taken from donors at this early stage of infection conferred protection against homologous challenge. This was manifested in both competent and sublethally irradiated recipients as a reduced level and quickened remission of primary parasitaemia, and as a more rapid clearance of pRBC from the blood stream, compared to control mice receiving unprimed lymphocytes. Although it was possible to transfer immunity with preparations enriched for either T or B cells, optimal protection was conferred by an unfractionated population containing both lymphocyte phenotypes, suggesting that there was a degree of synergistic activity between parasite-primed T and B cells in the control of malarial infection. This concept was supported further by examination of serum Ab titres for recipients of semi-immune T, B or T & B spleen cells. In each instance, the level of specific anti-P. c. chabaudi AS Ig reached a peak between d 31-33 p. i. , at or just prior to recrudescence, but the highest titres were recorded for recipients of a mixed splenic population. Since serum Ig levels were quite low during the first wave of patent parasitaemia, it suggested that resolution of acute infection was achieved largely through Ab-independent mechanisms of immunity. This correlated well with a significantly quicker remission of primary parasitaemia observed in sublethally irradiated recipients of semi-immune T cells, compared to similarly treated mice receiving the same inoculum size of either B or T & B cells. To dissect further the protective immune response in this model, splenic T lymphocytes were taken from P. c. chabaudi AS strain-infected NIH mice on d 16 and d 20 of primary infection and after resolution of secondary and tertiary infections, and each of these preparations established as cell lines in vitro using a lysed extract of pRBC as the source of antigenic stimulation. All four lines were maintained in long term culture and all proliferated specifically in response to P. c. chabaudi AS Ag processed and presented by syngeneic APC. It was shown that recognition of the APC/Ag complex by T cells was an MHC class ll-restricted phenomenon, each cell line requiring APC of compatible H-2 haplotype for an in vitro proliferative response. By using surface immunofluorescence and the complement-mediated cytotoxicity assay, each line was characterised phenotypically as Ly-4+, i. e. belonging to the helper/inducer T cell subset. In vivo, adoptive transfer of each Ly-4+ line was effective in conferring protective immunity to naive and to immunocompromised mice. This was demonstrable, compared to controls given naive T and/or B cells, as both a reduced level and shortened duration of primary parasitaemia, and as a quicker parasite elimination. Inoculation of the P. c. chabaudi AS-reactive lines into non-immune mice challenged with genotypic or phenotypic variant pRBC indicated that there was a strain-specific element of the immunity transferred. Although mice were able to control infection with heterologous parasites, the greatest protection was conferred against challenge with the homologous pRBC to which the lines had been raised. For the two Ly-4+ lines taken from reinfected mice, the protective activity against P. c. chabaudi AS challenge upon adoptive transfer into adult-thymectomised, irradiated and bone marrow-reconstituted mice was improved significantly by the cotransfer of additional naive B cells. This suggested that these Ly-4-bearing lymphocytes act by Ab-mediated mechanisms in vivo. (Abstract shortened by ProQuest.)

Contamination of Emergency Medical Vehicles and Risk of Infection to Paramedic First Responders and Patients by Antibiotic-Resistant Bacteria: Risk Evaluation and Recommendations from Ambulance Case Studies

Contamination of emergency medical vehicles with pathogenic microbes poses a potential threat to public health considering the many millions of ambulance responses that are made globally each year. This risk of infection is to the patients, to their companions who may travel with them, and to the paramedic first responders whose work involves pre- or inter-hospital transfer. This applies particularly to contamination by those infectious disease-causing microbes for which the threat is heightened because of their recognized resistance to leading antimicrobial agents. Determining the risks should facilitate the advancement of best practices to enhance infection control of routine outbreaks and during a major emergency such as a disease pandemic or a bioterrorism event. This may merit the introduction of amended guidelines for ambulance cleaning and disinfection to achieve more effective pre-hospital infection control among the worldwide community of emergency service providers

Diagnosis of Dengue: Strengths and Limitations of Current Techniques and Prospects for Future Improvements

Dengue is an increasingly common mosquito-borne, flaviviral disease of significant public health concern. The disease is endemic throughout tropical and subtropical regions, placing almost half of the world’s population at risk, and each year approaching 100 million people in around 130 countries are infected. There is acknowledged to be four antigenically distinct serotypes of the virus, and arguably a fifth, each of which elicits a full spectrum of clinical disease. This ranges from asymptomatic self-limiting infection to life-threatening severe manifestations characterized by plasma leakage, bleeding, and/or organ failure. Recovery from primary infection by one serotype provides life-long immunity against reinfection by that particular serotype, whereas with subsequent infections by other serotypes, the risk of developing severe dengue is increased. Rising mortality and morbidity rates caused by infection in recent years are attributable partly to a lack of availability of effective antiviral therapies and vaccines. In this context, early detection of infection with sensitive and specific laboratory tools and the prompt clinical management of this disease is a health care priority. Although a variety of techniques are currently used for laboratory diagnosis of dengue, no single methodology satisfies the ideal requirement for both sensitivity and specificity, while also being rapid and inexpensive. Newer detection tools that can fill this acknowledged gap in dengue diagnosis are urgently required

Prospects and Pitfalls of Pregnancy-Associated Malaria Vaccination Based on the Natural Immune Response to Plasmodium falciparum VAR2CSA-Expressing Parasites

Pregnancy-associated malaria, a manifestation of severe malaria, is the cause of up to 200,000 infant deaths a year, through the effects of placental insufficiency leading to growth restriction and preterm delivery. Development of a vaccine is one strategy for control. Plasmodium falciparum-infected red blood cells accumulate in the placenta through specific binding of pregnancy-associated parasite variants that express the VAR2CSA antigen to chondroitin sulphate A on the surface of syncytiotrophoblast cells. Parasite accumulation, accompanied by an inflammatory infiltrate, disrupts the cytokine balance of pregnancy with the potential to cause placental damage and compromise foetal growth. Multigravid women develop immunity towards VAR2CSA-expressing parasites in a gravidity-dependent manner which prevents unfavourable pregnancy outcomes. Although current vaccine design, targeting VAR2CSA antigens, has succeeded in inducing antibodies artificially, this candidate may not provide protection during the first trimester and may only protect those women living in areas endemic for malaria. It is concluded that while insufficient information about placental-parasite interactions is presently available to produce an effective vaccine, incremental progress is being made towards achieving this goal

Host-Virus Interactions in Dengue Infection indicate Targets for Detection and Therapeutic Interventions

Dengue is a mosquito-transmitted viral infectious disease that is endemic to 110 countries spanning tropical and subtropical regions. While infection is typically asymptomatic, symptoms of the estimated 50-100 million clinical cases are often debilitating and occasionally life-threatening, resulting in as many as 5 million hospitalisations annually. Consequently, the World Health Organization regards dengue as a significant global public health concern. Immense challenges exist in both formulating and constructing an efficacious vaccine for prophylaxis and in developing therapeutics for cure. Although there have been numerous molecular studies of the interaction between host and virus, and the metabolic pathways of several proteins are implicated in dengue virus replication, their biological significance remains unclear. It is important to consider clinical, immunopathological and epidemiological features to decipher the complexity of disease and to unravel the mechanisms attributed to its progression. This editorial emphasises the critical events causing vascular endothelial permeability, which underpins the manifestations in humans of dengue haemorrhagic fever and dengue shock syndrome

Vaccine Development against Dengue, a Viral Disease of Increasing Significance to Global Public Health

Dengue is a mosquito-borne viral disease of humans that is a major public health concern in tropical and subtropical regions of the world. The increasing mortality and morbidity rates caused by infection in recent years are attributable partly to a lack of availability of effective antiviral therapies and vaccines. In a concerted attempt to arrest this global expansion, several dengue vaccine candidates have progressed from pre-clinical testing into clinical trials. However, the advancement of vaccine development has manifest challenges to be overcome. A principal tenet underpinning dengue vaccine design is balanced immunity to all five recognised virus serotypes, but difficulties in achieving optimal attenuation of each virus and interference between individual attenuated viruses are significant hurdles to successful implementation. Currently, the most advanced vaccine candidate, the recombinant, live-attenuated ChimeriVax-DEN1-4 preparation developed by Sanofi Pasteur, is likely to achieve licensure at the completion of phase III trials and undergo population safety surveillance. Subunit and DNA vaccines are also in various stages of clinical evaluation. The intrinsic rationale is to produce a safe, efficacious and cost-effective vaccine. While this remains an achievable goal, progress is limited by an incomplete understanding of dengue viral pathogenesis, together with a lack of suitable animal models for fundamental pre-clinical development. This editorial highlights current approaches and future directions for vaccine strategies to combat the global expansion of this infectious disease

Interplay between T Regulatory and T Helper 17 Lymphocytes in Modulation of Immunity to Blood Stage Malaria Infection

Malaria claims millions of lives worldwide each year. While a pro-inflammatory immune response is required to control parasite replication and promote clearance of infected erythrocytes, considerable disease pathology is caused by an excessive and dysregulated inflammatory reactivity to blood stage infection. Clinical symptoms, including fever and chills, correspond to production by CD4+ T helper (Th) lymphocytes of high levels of pro-inflammatory cytokines including tumour necrosis factor-α, interleukin-12 and interferon- γ in response to parasite components released upon erythrocyte rupture. Differentiation into specific effector Th subsets is directed by polarizing cytokines and expression of master transcription factors. From a perspective of homeostasis, further regulatory Th subsets have been described that secrete specific cytokines to modulate the effector immune response and thus play a pivotal role in protecting the body from direct and indirect pathogenic effects of malaria infection. In particular, T regulatory (Treg) lymphocytes are associated with immune tolerance and play a crucial role in suppressing the host response by inhibiting the function of effector subsets such as Th1 and Th17. This prevents inflammation produced downstream by (non-T) effectors cells. Treg lymphocytes, exemplified by CD4+CD25+Foxp3+ cells, gradually increase in number during infection to achieve and maintain the homeostasis of an otherwise imbalanced T cell response. This editorial discusses the production of Treg and Th17 lymphocytes and the interrelated roles played by their signature cytokines during malaria infection and considers the contribution of each to parasite clearance or progression

Burden of antibiotic resistance among children with typhoid in Gadap Town, Karachi, Pakistan

Background: Increasing antibiotic resistance by pathogenic bacteria is observed in poor sanitary conditions. The peak incidence of typhoid occurs between 5–15 years of age. This is the most common bacteraemic illness of children in Pakistan. The aim of this study was to investigate the frequency of drug-resistant SalmonellaTyphi and S. Paratyphi A in children hospitalized or treated as outpatients at a tertiary care centre that serves Gadap Town, an extensive slum district of Karachi. Methods: A total of 275 peripheral blood samples were collected from children up to 14 years old who presented with clinical features of typhoid to Fatima Hospital, Baqai Medical University, over a two-year period. Samples were cultured for growth of aerobic and facultative anaerobic bacteria, identified by biochemical reactions. Antimicrobial susceptibility was tested by Kirby-Bauer disc diffusion using eight different antibiotics. Results: Among all samples, 30 (10.9%) were positive for S. Typhiby blood culture. The rate of positivity was 23 (76.7%) cases for ages 5–14 years, three (10.0%) in each of age groups 2.0–2.9 and 4.0–4.9 years, and one patient (3.3%) aged 3.0–3.9 years. The majority of S. Typhi isolates were resistant to co-trimoxazole (66.7%), ampicillin (63.3%), nalidixic acid (60.0%), chloramphenicol (50.0%) and aztreonam (50.0%). However, most isolates were susceptible to ceftriaxone (76.7%) and ciprofloxacin (66.7%). There were 15 multidrug-resistant isolates but no typhoid-related deaths. Conclusion: Our findings show evidence of antimicrobial resistance by S. Typhiisolated from Karachiite children living in a poverty-stricken setting where water quality and sanitation are both unsatisfactory. Currently, Pakistan’s most populated city is recognized as a focus of typhoid cases. Therefore, this first report of the emergence of confirmed cases of multidrug-resistant S. Typhi from the only public hospital in its largest neighborhood identifies a grave public health concern