Breakthrough COVID-19 infections - Analyzing our experience.

Objective: There are many cases of post-vaccination COVID-19 globally. Also, literature on serum antibodies after vaccination is abundant. Our research focuses on breakthrough infections reported at our institution during the third wave of COVID-19. Methods: A total of 177 people recruited at the Indus Hospital Karachi between May to September 2021 with COVID-19 infection were divided into vaccinated, partially vaccinated, and unvaccinated cohorts. Furthermore, a subset of the vaccinated cohort was tested for anti-NP and anti-S antibodies. Results: There were 119 patients with breakthrough infection, however, 74% had mild symptoms. The antibodies against NP and S were found at a higher level in those who had a breakthrough infection in comparison to healthy vaccinated controls. Conclusion: Vaccination does not prevent disease but does confer some immunity causing less severe infection.

Clinical spectrum and outcomes of patients with different resistance patterns of Salmonella enterica.

Background and Objective: Unceasing rise in cases of enteric fever, in particular extensively drug resistant (XDR) strain of Salmonella enterica, has led to a growing threat, leaving only carbapenems and azithromycin as the precious option. In this regard, we determined the burden and clinical course of XDR salmonella in comparison to multidrug-resistant (MDR) and drug sensitive (DS) strains. Methods: A retrospective chart review of 1515 Salmonella Typhi (S.typhi) culture positive patients was conducted at Indus Hospital and Health Network, Karachi from July 2017 to December 2018. Results: During our study, we observed children at the age of 5-6 years and adults at the age of 20-22 years were the chief targets of S.typhi. Further, we witnessed a rapid shift of drug resistance from MDR to XDR over the one year of study. Almost all patients presented with fever. However other signs and symptoms like malaise, body aches, anorexia, diarrhea, vomiting and abdominal pain were more common in XDR Typhoid patients. Further, the need of hospitalization, total hospital stay and mortality was also greater for XDR typhoid patients. Conclusion: There is a crucial requirement for consolidated steps to curtail the spread of XDR Salmonella tyhi disease as its management is challenging, and it is associated with increased morbidity and mortality.

Effect of Remdesivir on mortality and length of stay in hospitalized COVID-19 patients: A single center study.

Objectives: To see the difference in mortality among hospitalized COVID-19 patients given Remdesivir (RDV) with those who were not given RDV. Methods: A prospective cohort study was conducted on patients who were admitted to the COVID-19 isolation unit at The Indus Hospital, Korangi Campus Karachi between March and June 2020. Results: Groups were similar in age and gender distribution. RDV group was more hypoxic, had severe ARDS and needed higher Oxygen support compared to non-RDV group (p=0.000). Median SOFA score was 2 in RDV vs 5 in non-RDV (p=0.000). More than moderate COVID pneumonia was found in 92% of the RDV group while 89% of non-RDV group (p value=0.001). Median day of illness to administer Remdesivir was 10. There was no difference in mortality (45.5% in RDV vs 40.4% in non-RDV; p=0.4) between the two groups. Median length of hospital stay was 12 days (IQR=7.5-14.5) in RDV group compared to 10 days (IQR=6-14) in non-RDV group (p=0.009). Conclusion: RDV did not show any difference in in-hospital mortality in our patients. More patients had severe ARDS in the RDV group while patients in the non-RDV group had higher SOFA score and multi-organ failure. Length of stay was longer in patients receiving Remdesivir.

Frequency, clinical characteristics, risks, and outcomes of Paradoxical upgrading reactions during anti-tuberculosis treatment in tuberculous lymphadenitis.

OBJECTIVES: To investigate the clinical characteristics, risks and outcomes of Paradoxical upgrading reactions (PUR) during anti-tuberculosis treatment (ATT) in superficial tuberculous lymphadenitis (TBLA). METHODS: In this nested case-control study, all patients diagnosed with TBLA based on combinations of histopathology, acid-fast bacilli (AFB) microscopy, AFB culture, and GeneXpert, between February 2013 and April 2016, were enrolled. Standard ATT was given. Demographics, clinical characteristics, occurrence of PUR and outcome were recorded. RESULTS: TBLA was diagnosed and treated in 189 patients. PUR developed in 33 (17%), of which 77% developed new inflamed glands, 20.6% had increased size and inflammation of pre-existing glands and 5.9% had superficial chest wall abscesses requiring aspiration. All responded to regular NSAIDs except one, where a steroid course was effective. No change in dose or duration of ATT was required. Presence of anorexia (OR; 95%CI: 2.6; 1.003-6.74), bilateral extensive lymphadenopathy (OR; 95%CI: 2.9; 1.1-7.5) and lymph node specimen positive for AFB (OR; 95%CI: 3.2; 1.04-10.1) were significantly associated with PUR. CONCLUSION: PUR is common in TBLA. It responded to NSAIDS and does not need any modification in ATT.

Response to: regarding the significance of anti-COVID-IgA antibody response in COVID-19 breakthrough infection.

In response to Chen et al.'s comments on our paper regarding the significance of anti-COVID-IgA antibody response in COVID-19 breakthrough infection in vaccinated patients, we have highlighted the role and the scope of this paper in this correspondence. The role of anti-COVID-19-IgA is already known. The objective of the previous study was to see its role in breakthrough-infected patients. To analyse this effect, we recruited patients with COVID-19 infection after they were fully vaccinated and compared them with the vaccinated group who did not get the infection. Both groups were equally exposed to the virus as all of them were health care workers. We also showed that the anti-COVID-19-NP-IgA was absent in the healthy cohort of our study groups, signifying the absence of natural infection in them during this period. The article also highlights the importance of vaccinating all individuals including those who are immunosuppressed, as it prevents severe COVID-19 infection in these individuals. The physicians should be aware of the fact that immunosuppressed patients are more likely to get COVID-19 breakthrough infection. However, proper vaccination with booster doses prevents severe infection in them.

Significance of Anti-COVID-IgA antibody response in COVID-19 breakthrough infection in vaccinated patients - a single-centered study from Pakistan.

An increasing number of breakthrough-COVID-19-vaccinated individuals are being reported across the world. Humoral immunity has a crucial role in combating infection. In this study, we aimed to assess the importance of anti-COVID-S1-IgA and anti-COVID-NP-IgA in confirmed COVID-19 after vaccination (breakthrough infection group). Blood samples were collected from the breakthrough infection group within one week of breakthrough infections (n = 34). A second sample was also collected after 4 to 8 weeks (n = 27). Blood samples of healthy individuals (n = 29) were collected 4-8 weeks after the completion of vaccination. Anti-COVID-S1-IgA and anti-COVID-NP-IgA were detected by ELISA. Statistical analysis was performed using IBM SPSS version 24. In this study, we found a higher positivity rate for anti-COVID-S1-IgA in the breakthrough infection group (70% vs. 28% in healthy individuals). Anti-COVID-NP-IgA was not found in the control group (11% in the breakthrough infection group vs. 0 in healthy individuals). In the breakthrough-infected group, the positivity rate of anti-COVID-NP-IgA decreased significantly (median titers 16.9 IU/ml decreased to 4.2 IU/ml) p = 0.001), while anti-COVID-S1-IgA increased over a period of 4-8 weeks (9.35-16.35 IU/ml). Importantly, IgA response to both COVID-19 NP and S1 antigens was not found in 13 patients at initial testing. The findings of this study show that serum IgA may have a role both in breakthrough infections and also in the prevention of severe infection. Sluggish anti-COVID-19-IgA antibody response may be responsible for the occurrence of COVID-19 infection in breakthrough infection. On the other hand, more sustained anti-COVID-19-S1-IgA over a longer period of time may have a role in preventing these patients from severe infections and hospitalization. However, a study on a larger sample size including patients with severe disease after vaccination is required to prove this hypothesis. To the best of our knowledge, this is the first study reporting the importance of serum IgA in breakthrough-infected patients from our region.

Comparative effectiveness of adding delamanid to a multidrug-resistant tuberculosis regimen comprised of three drugs likely to be effective.

Clarity about the role of delamanid in longer regimens for multidrug-resistant TB is needed after discordant Phase IIb and Phase III randomized controlled trial results. The Phase IIb trial found that the addition of delamanid to a background regimen hastened culture conversion; the results of the Phase III trial were equivocal. We evaluated the effect of adding delamanid for 24 weeks to three-drug MDR/RR-TB regimens on two- and six-month culture conversion in the endTB observational study. We used pooled logistic regression to estimate the observational analogue of the intention-to-treat effect (aITT) adjusting for baseline confounders and to estimate the observational analogue of the per-protocol effect (aPP) using inverse probability of censoring weighting to control for time-varying confounding. At treatment initiation, 362 patients received three likely effective drugs (delamanid-free) or three likely effective drugs plus delamanid (delamanid-containing). Over 80% of patients received two to three Group A drugs (bedaquiline, linezolid, moxifloxacin/levofloxacin) in their regimen. We found no evidence the addition of delamanid to a three-drug regimen increased two-month (aITT relative risk: 0.90 (95% CI: 0.73-1.11), aPP relative risk: 0.89 (95% CI: 0.66-1.21)) or six-month culture conversion (aITT relative risk: 0.94 (95% CI: 0.84, 1.02), aPP relative risk: 0.93 (95% CI: 0.83, 1.04)). In regimens containing combinations of three likely effective, highly active anti-TB drugs the addition of delamanid had no discernible effect on culture conversion at two or six months. As the standard of care for MDR/RR-TB treatment becomes more potent, it may become increasingly difficult to detect the benefit of adding a single agent to standard of care MDR/RR-TB regimens. Novel approaches like those implemented may help account for background regimens and establish effectiveness of new chemical entities.

Is Tocilizumab An Effective Therapy For Severe Covid-19: A Single Center Study.

Background: The quest for effective therapies in Covid-19 continues. We compared the outcome of severe COVID-19 patients treated with and without Tocilizumab, an IL-6 inhibitor. Methods: This is a prospective cohort study on the clinical characteristics and outcomes of patients with Covid-19 patients admitted at The Indus Hospital and Health Network, Karachi between 24th March and 19th June 2020. Adult patients who received TCZ were compared with respect to mortality and days of hospitalization with those who did not. Results: A total of 88 patients including 41 patients in the TCZ group and 47 in non-TCZ group were recruited. Baseline demographic characteristics were comparable. TCZ group patients presented with worse clinical features including median SpO2 82% vs 88%, p<0.05 and CRP 193 vs 133.9 mg/L, p<0.05. Approximately, 85.4% were admitted in ICU compared to 69.8% in non-TCZ group, p>0.05. Mortality was not different among the groups (46% in TCZ group vs 51.1% in non-TCZ group, p>0.05). Median length of hospital stays, days of intubation, use of inotropic agents, and use of invasive ventilation or in-hospital complications were similar between the groups. Sub-group analysis revealed that mortality within TCZ group was associated with high IL-6 levels (173 vs 69.66 pg/ml, p<0.05), ICU admission (100% vs 72%, p<0.05), need for mechanical ventilation (100% vs 13.6%, p<0.05) and higher incidence of in-hospital complications, p<0.05. Conclusion: TCZ failed to demonstrate any mortality benefit in our patients. Non-survivors within the TCZ group were more critical compared to survivors and developed more in hospital complications.

Neutralizing Antibody Response to BBIBP-CorV in Comparison with COVID-19 Recovered, Unvaccinated Individuals in a Sample of the Pakistani Population.

Fifty five percent of the Pakistani population is still unvaccinated with the two-dose protocol of COVID-19 vaccines. This study was undertaken to determine the seroconversion rate and antibody titers following the two-dose BBIBP-CorV protocol, and to compare these variables in unvaccinated, COVID-19 recovered individuals (total n = 180) at Indus Hospital and Health Network, Karachi. Pseudotyped lentivirus antibody neutralization assays and SARS-CoV-2 IgG Quant II (Abbott) immunoassays were performed 4-8 weeks following the second dose of the BBIBP-CorV or PCR positivity/onset of symptoms of COVID-19. Seroconversion rate, using neutralization assays, in vaccinated individuals was lower (78%) than that in unvaccinated, COVID-19-recovered individuals with moderate to severe infection (97%). Prior PCR positivity increased serocoversion rate to 98% in vaccinated individuals. Immunoassays did not, however, reveal significant inter-group differences in seroconversion rates (≥95% in all groups). Log10 mean antibody neutralizing titers following the two-dose BBIBP-CorV protocol (IC50 = 2.21) were found to be significantly less than those succeeding moderate to severe COVID-19 (IC50 = 2.94). Prior SARS-CoV-2 positivity significantly increased post-vaccination antibody titers (IC50 = 2.82). Similar inter-group titer differences were obtained using the immunoassay. BBIBP-CorV post-vaccination titers may, thus, be lower than those following natural, moderate to severe infection, while prior SARS-CoV-2 exposure increases these titers to more closely approximate the latter.

WHO Point Prevalence Survey to Describe the Use of Antimicrobials at a Tertiary Care Center in Pakistan: A Situation Analysis for Establishing an Antimicrobial Stewardship Program.

Antimicrobial stewardship is a systematic approach for promoting and monitoring responsible antimicrobial use globally. We conducted a prospective point prevalence survey of antimicrobial utilization among hospitalized adult patients during September 2021. The survey instrument was adapted from the WHO methodology for point prevalence surveys, and it was conducted at The Indus Hospital and Health Network, Karachi. Among the 300 admitted patients, 55% were males and the mean age was 44 (±18) years. At least 67% of the patients received one antimicrobial agent and the most common indication was surgical prophylaxis (40%). The most frequently used were antibacterial agents (97%) among all antimicrobials. Amoxicillin/Clavulanic acid and Ceftriaxone were the most frequently used antibacterial agents, i.e., 14% each. At least 56% of the antibacterial agents were amenable to antimicrobial stewardship when reviewed by infectious disease (ID) experts. Reasons for stewardship were: antibacterial not indicated (n = 39, 17.0%), unjustified prolonged duration of antibacterial (n = 32, 13.9%), extended surgical prophylaxis (n = 60, 26.2%), non-compliance to surgical prophylaxis guidelines (n = 30, 13.1%), and antibacterial not needed on discharge (n = 27, 11.7%). Median days of therapy (DOT) per agent was 3 days (IQR 2-4), while median DOT per patient was 2 days (IQR 1-4). These data have described the pattern of antimicrobial utilization in our institute. We found a higher prevalence of antimicrobial use overall as compared to the global figures, but similar to other low- and middle-income countries. Two important areas identified were the use of antimicrobials on discharge and extended surgical prophylaxis. As a result of these data, our institutional guidelines were updated, and surgical teams were educated. A post-intervention survey will help us to further determine the impact. We strongly recommend PPS at all major tertiary care hospitals in Pakistan for estimating antimicrobial utilization and identifying areas for stewardship interventions.

Determinants of in-hospital mortality in COVID-19; a prospective cohort study from Pakistan.

A prospective cohort study was conducted at the Indus Hospital Karachi, Pakistan between March and June 2020 to estimate the in-hospital mortality among hospitalized COVID-19 patients and its determinants. A total of 170 adult patients were enrolled and all-cause mortality was found to be 39% (67/170). Most non-survivors were above 60 years of age (64%) while gender distribution was quite similar in both groups (males: 77% vs 78%). Most (80.6%) non-survivors came with peripheral oxygen saturation less than 93% while 95% of them had critical disease on arrival. Use of non-invasive ventilation in emergency room was higher among non-survivors (56.7%) versus survivors (26.2%). Median Interleukin-6 levels were higher among non-survivors (78.6: IQR = 33.8-49.0) compared to survivors (21.8: IQR = 12.6-36.3). Most patients in the non-survivor group (86.6%) required invasive ventilator support during hospital stay compared to 7.8% in the survivors. The median duration of ICU stay was longer for non-survivors (9: IQR = 6-12) compared to survivors (5: IQR = 3-7) days. Univariable binary logistic regression showed that age above 60 years, oxygen saturation below 93%, Neutrophil to lymphocyte ratio above 5, procalcitonin above 2ng/ml, unit increase in SOFA score and arterial lactate levels were associated with mortality. We also found that a unit decrease in Pao2/FiO2 ratio and serum albumin were associated with mortality in our patients. Multivariable regression showed that age above 60 years (aOR = 3.4: 95% CI = 1.6-6.9), peripheral oxygen saturation below 93% (aOR = 3.5:95% CI = 1.6-7.7) and serum pro-calcitonin above 2ng/ml (aOR = 4.8; 95% CI = 1.9-12.2) were associated with higher odds of mortality when adjusted by month of admission. Most common cause of death was multisystem organ failure in 35 (56.6%) non-survivors while 22 (35.5%) died due to respiratory failure. Larger prospective studies are needed to further strengthen these findings.

Clinical manifestation and outcomes of multi-drug resistant (MDR) Raoultella terrigena infection - A case series at Indus Health Network, Karachi, Pakistan.

BACKGROUND AND OBJECTIVES: There is paucity of literature available on Raoultella terrigena infection. Microbiological identification of Raoultella terrigena is difficult and isolates are frequently misidentified as Klebsiella species. This series of 3 cases with Raoultella terrigena septicemia provides a description of the pitfalls and challenges in the diagnosis and management of the highly resistant strains isolated and to the best of our knowledge, is the first report from Pakistan. METHODS: The medical records of 3 cases of R. terrigena reported in the hospital over two months were reviewed retrospectively to record all relevant clinical information. Organism was identified by using Analytical profile index (API) 20 E with 90-95% successful identification and the sensitivity testing was performed by disc diffusion method. RESULTS: This organism caused fulminant sepsis in case 2 resulting in mortality and complicated urinary tract infection in the third, while in case 1 it preceded the fatal candidemia. All three patients were females who had multiple co-morbid and had a history of protracted hospital stay and antibiotic usage elsewhere before being shifted to our hospital. The isolates were resistant to all beta lactams and were even colistin resistant in two patients, creating challenges and suboptimal response for effective antibiotic therapy. CONCLUSIONS: The purpose of this case series is to highlight the highly drug resistant profile of this organism and the fulminant infection it can cause, which if spreads in our hospitals due to breaches in infection control practices, can pose risk as a deadly and untreatable nosocomial infection.

An Unusual Case of Extensively Drug Resistant Typhoid Fever.

Enteric fever is a potentially fatal multisystemic illness caused primarily by Salmonella typhi and, to a lesser extent, by Paratyphi A, B, and C. Emergence of resistance has depleted the antimicrobial arsenal overtime, making treatment challenging and costly. In 2016, a new extensively drug resistant (XDR) strain of Salmonella typhi emerged in Sindh, which only responds to two antibiotics--carbapenems and azithromycin. Its clinical spectrum is not yet clear but increased morbidity and mortality is being observed with it. We present a severe case of XDR Salmonella typhi where the clinical course was complicated by delayed defervescence, severe hepatitis, soft tissue infection, and profuse lower gastrointestinal bleeding, which responded to a combination of carbapenem and azithromycin and an invasive procedure to contain bleeding from the cecal artery. The purpose of this case report is to highlight the morbidity, cost, and therapeutic challenges associated with severe XDR Salmonella typhi infection.

Histopathological and microbiological findings and diagnostic performance of GeneXpert in clinically suspected tuberculous lymphadenitis.

OBJECTIVES: The primary objective was to determine the association between histopathological and microbiological findings in patients clinically suspected to have tuberculous lymphadenitis. A secondary objective was to assess the diagnostic utility of GeneXpert in lymph node specimens. METHOD: This was a single-centre prospective cohort study, performed in the Infectious Disease Clinic at The Indus Hospital. Three hundred and forty-one adult patients with chronically enlarged, accessible lymph nodes were enrolled after obtaining verbal consent, between February 2013 and April 2016. Tissue specimens were processed for histopathology, acid-fast bacillus (AFB) microscopy, AFB culture, and GeneXpert. Based on these results, anti-tuberculosis therapy (ATT) was prescribed. Clinical characteristics and treatment outcomes were recorded. RESULTS: There were 297 evaluable patients; 74.4% were diagnosed with tuberculous lymphadenitis (TBLA), 6.7% with a malignancy, and 12.8% with reactive nodes. TBLA was diagnosed on suggestive histopathology in 89.6% of cases, followed by GeneXpert (32.6%), mycobacterial culture (26.6%), and AFB smear positivity (12.5%). The sensitivity of GeneXpert was 65.7% when assessed against AFB culture. Drug resistance was displayed by 8.2% of GeneXpert-positive cases and 11.7% of culture-positive cases. The majority of TBLA patients (88.7%) responded favorably to ATT. CONCLUSIONS: In light of laboratory evidence, a quarter of patients suspected of TBLA had an alternative diagnosis, highlighting its importance in avoiding over-treatment and diagnostic delays in malignancy. Although sensitivity is poor, the demonstration of drug resistance by both GeneXpert and AFB culture represents a useful tool to guide treatment.