Prevalence of co-existent COVID-19-associated pulmonary aspergillosis (CAPA) and its impact on early mortality in patients with COVID-19-associated pulmonary mucormycosis (CAPM).

BACKGROUND: Data on mixed mould infection with COVID-19-associated pulmonary aspergillosis (CAPA) and COVID-19-associated pulmonary mucormycosis (CAPM) are sparse. OBJECTIVES: To ascertain the prevalence of co-existent CAPA in CAPM (mixed mould infection) and whether mixed mould infection is associated with early mortality (≤7 days of diagnosis). METHODS: We retrospectively analysed the data collected from 25 centres across India on COVID-19-associated mucormycosis. We included only CAPM and excluded subjects with disseminated or rhino-orbital mucormycosis. We defined co-existent CAPA if a respiratory specimen showed septate hyphae on smear, histopathology or culture grew Aspergillus spp. We also compare the demography, predisposing factors, severity of COVID-19, and management of CAPM patients with and without CAPA. Using a case-control design, we assess whether mixed mould infection (primary exposure) were associated with early mortality in CAPM. RESULTS: We included 105 patients with CAPM. The prevalence of mixed mould infection was 20% (21/105). Patients with mixed mould infection experienced early mortality (9/21 [42.9%] vs. 15/84 [17.9%]; p = 0.02) and poorer survival at 6 weeks (7/21 [33.3] vs. 46/77 [59.7%]; p = 0.03) than CAPM alone. On imaging, consolidation was more commonly encountered with mixed mould infections than CAPM. Co-existent CAPA (odds ratio [95% confidence interval], 19.1 [2.62-139.1]) was independently associated with early mortality in CAPM after adjusting for hypoxemia during COVID-19 and other factors. CONCLUSION: Coinfection of CAPA and CAPM was not uncommon in our CAPM patients and portends a worse prognosis. Prospective studies from different countries are required to know the impact of mixed mould infection.

Target product profiles for diagnosis of sepsis: Proposing a new approach for diagnostic innovation.

Background & objectives: Sepsis, including neonatal sepsis, remains a prevalent cause of morbidity and mortality in low- and middle-income countries such as India, representing 85 per cent of all sepsis-related deaths globally. Early diagnosis and timely initiation of treatment is challenging due to non-specific clinical manifestations and non-availability of rapid diagnostic tests. There is an urgent need for affordable diagnostics with fast turnaround time catering to the needs of end-users. Target product profiles (TPPs) have been found instrumental in developing 'fit-for-use' diagnostics, thus reducing the time taken to facilitate development and improving diagnosis. Hitherto, no such guidance or criteria has been defined for rapid diagnostics for sepsis/neonatal sepsis. We propose an innovative approach for developing the diagnostics for sepsis screening and diagnosis which can be utilized by diagnostic developers in the country. Methods: Thr@ee-round Delphi method, including two online surveys and one virtual consultation, was adopted to define criteria for minimum and optimum attributes of TPPs and build consensus on characteristics. Expert panel (n=23) included infectious disease physicians, public health specialists, clinical microbiologists, virologists, researchers/scientists and technology experts/innovators. Results: We present a three-component product profile for sepsis diagnosis, (i) screening with high sensitivity, (ii) detection of aetiological agent, and (iii) profiling of antimicrobial susceptibility/resistance, in adults and neonates with an option of testing different considerations. An agreement of >75 per cent was achieved for all TPP characteristics by Delphi. These TPPs are tailored to the Indian healthcare settings and can also be extrapolated to other resource-constraint and high-disease burden settings. Interpretation & conclusions: Diagnostics developed using these TPPs will facilitate utilization of invested resources leading to development of the products that have potential to ease the economic burden on patient and save lives.

Multicenter Epidemiologic Study of Coronavirus Disease-Associated Mucormycosis, India.

During September-December 2020, we conducted a multicenter retrospective study across India to evaluate epidemiology and outcomes among cases of coronavirus disease (COVID-19)-associated mucormycosis (CAM). Among 287 mucormycosis patients, 187 (65.2%) had CAM; CAM prevalence was 0.27% among hospitalized COVID-19 patients. We noted a 2.1-fold rise in mucormycosis during the study period compared with September-December 2019. Uncontrolled diabetes mellitus was the most common underlying disease among CAM and non-CAM patients. COVID-19 was the only underlying disease in 32.6% of CAM patients. COVID-19-related hypoxemia and improper glucocorticoid use independently were associated with CAM. The mucormycosis case-fatality rate at 12 weeks was 45.7% but was similar for CAM and non-CAM patients. Age, rhino-orbital-cerebral involvement, and intensive care unit admission were associated with increased mortality rates; sequential antifungal drug treatment improved mucormycosis survival. The COVID-19 pandemic has led to increases in mucormycosis in India, partly from inappropriate glucocorticoid use.

Predicting Postpartum Hemorrhage (PPH) during Cesarean Delivery Using the Leicester PPH Predict Tool: A Retrospective Cohort Study.

OBJECTIVE: The aim of the present study was to develop a toolkit combining various risk factors to predict the risk of developing a postpartum hemorrhage (PPH) during a cesarean delivery. STUDY DESIGN: A retrospective cohort study of 24,230 women who had cesarean delivery between January 2003 and December 2013 at a tertiary care teaching hospital within the United Kingdom serving a multiethnic population. Data were extracted from hospital databases, and risk factors for PPH were identified. Hothorn et al recursive partitioning algorithm was used to infer a conditional decision tree. For each of the identified combinations of risk factors, two probabilities were calculated: the probability of a patient producing ≥1,000 and ≥ 2,000 mL blood loss. RESULTS: The Leicester PPH predict score was then tested on the randomly selected remaining 25% (n = 6,095) of the data for internal validity. Reliability testing showed an intraclass correlation of 0.98 and mean absolute error of 239.8 mL with the actual outcome. CONCLUSION: The proposed toolkit enables clinicians to predict the risk of postpartum hemorrhage. As a result, preventative measures for postpartum hemorrhage could be undertaken. Further external validation of the current toolkit is required.

What is New in the Diagnosis of Childhood Tuberculosis?

The fact that almost half of the 1 million cases of childhood tuberculosis (TB) globally remain undiagnosed jeopardizes the TB elimination goal. Fortunately, there are new advances in this field which have the potential to bridge this diagnostic gap. Advances in imaging include computer assisted interpretation of chest X-rays (CXRs), point of care ultrasound (POCUS) and faster and superior computed tomography/ magnetic resonance imaging (CT/ MRI) protocols. The urine lipoarabinomannan test has proved to be a good point of care test for diagnosing TB in Human immunodeficiency virus (HIV) infected children. Stool and nasopharyngeal aspirates are emerging as acceptable alternatives for gastric lavage and induced sputum for diagnosing intrathoracic tuberculosis. Xpert MTB/RIF Ultra has improved sensitivity compared to Xpert MTB/RIF for diagnosing both pulmonary/ extrapulmonary TB. Xpert XDR is another commercially available accurate point of care test for detecting resistance to drugs other than rifampicin in smear positive samples. Other molecular methods including new line probe assays, pyrosequencing, whole genome sequencing, and targeted next generation sequencing are extremely promising but not available commercially at present. The C-Tb skin test is an acceptable alternative to the tuberculin skin test and interferon gamma release assays for diagnosis of latent infection. There is an urgent need to incorporate some of these advances in the existing diagnostic algorithms of childhood TB.

Indian Academy of Pediatrics Consensus Statement on Diagnosis and Management of Bone and Joint Infections in Children.

JUSTIFICATION: Osteoarticular infections are fairly common in children but often these are associated with underdiagnosis, delayed diagnosis and improper management. This leads to an increased incidence of complications and poor outcomes. Given the paucity of standard protocols for the management of these children in the Indian context, Indian Academy of Pediatrics (IAP) has taken the initiative to formulate guidelines for the early diagnosis and rational management of bone and joint infections (BJIs). OBJECTIVES: To critically evaluate the current evidence and formulate consensus guidelines for the diagnosis and management of BJIs in children. PROCESS: A committee comprising of eminent national faculty from different parts of the country who are experts in the field of Pediatric Infectious Diseases, Pediatric Orthopedics and Musculoskeletal Radiology was constituted and duly approved by the IAP. On Jan 16, 2021, a virtual meeting was held and a detailed discussions were carried out regarding the need to formulate these guidelines. Subsequently, the expert group defined the key questions in the first stage followed by collection and review of scientific evidences including available national and international recommendations or guidelines. This was followed by detailed deliberation among group members and presentation of their recommendations. The same were finalized in an online meeting on Aug 01, 2021, and a consensus statement was developed and adopted by the group. STATEMENT: BJIs are medical emergencies that need early diagnosis and appropriate therapy to prevent long term sequelae like limb deformities. Bacterial infections like Staphylococcus aureus is the most common etiological agent. Nonspecific and subtle clinical manifestations make the diagnosis of pediatric BJIs more challenging. Diagnosis of BJIs is primarily clinical, supplemented by laboratory and radiological investigations. The choice of antibiotic(s), mode of administration and duration of therapy requires individualization depending upon the severity of infection, causative organism, regional sensitivity patterns, time elapsed between onset of symptoms and the child's presentation, age, risk factors and the clinical and laboratory response to treatment. There is paucity of appropriate guidelines regarding the diagnosis and management of BJIs in children in Indian context. Hence, the need for this expert consensus guidelines in Indian settings.

Risk factors, mortality, and predictors of survival in COVID-19-associated pulmonary mucormycosis: a multicentre retrospective study from India.

OBJECTIVES: To compare COVID-19-associated pulmonary mucormycosis (CAPM) with COVID-19-associated rhino-orbital mucormycosis (CAROM), ascertain factors associated with CAPM among patients with COVID-19, and identify factors associated with 12-week mortality in CAPM. METHODS: We performed a retrospective multicentre cohort study. All study participants had COVID-19. We enrolled CAPM, CAROM, and COVID-19 subjects without mucormycosis (controls; age-matched). We collected information on demography, predisposing factors, and details of COVID-19 illness. Univariable analysis was used to compare CAPM and CAROM. We used multivariable logistic regression to evaluate factors associated with CAPM (with hypoxemia during COVID-19 as the primary exposure) and at 12-week mortality. RESULTS: We included 1724 cases (CAPM [n = 122], CAROM [n = 1602]) and 3911 controls. Male sex, renal transplantation, multimorbidity, neutrophil-lymphocyte ratio, intensive care admission, and cumulative glucocorticoid dose for COVID-19 were significantly higher in CAPM than in CAROM. On multivariable analysis, COVID-19-related hypoxemia (aOR, 2.384; 95% CI, 1.209-4.700), male sex, rural residence, diabetes mellitus, serum C-reactive protein, glucocorticoid, and zinc use during COVID-19 were independently associated with CAPM. CAPM reported a higher 12-week mortality than CAROM (56 of the 107 [52.3%] vs. 413 of the 1356 [30.5%]; p = 0.0001). Hypoxemia during COVID-19 (aOR [95% CI], 3.70 [1.34-10.25]) and Aspergillus co-infection (aOR [95% CI], 5.40 [1.23-23.64]) were independently associated with mortality in CAPM, whereas surgery was associated with better survival. DISCUSSION: CAPM is a distinct entity with a higher mortality than CAROM. Hypoxemia during COVID-19 illness is associated with CAPM. COVID-19 hypoxemia and Aspergillus co-infection were associated with higher mortality in CAPM.

A case of Kytococcus schroeteri prosthetic valve endocarditis in a patient with COVID-19 infection.

64 years old male presented fever, gastrointestinal symptoms, COVID-19 infection with bioprosthetic mitral in situ, cardio embolic stroke 2 years ago. The 2 D ECHO showed a vegetation indicating infective endocarditis. Three paired blood cultures grew Kytococcus schroeteri. The organism was sensitive to Vancomycin, Teicoplanin, Gentamycin and Linezolid. Patient had multiorgan dysfunction which further deteriorated into failure, disseminated intravascular coagulation resulting into death of the patient.

Burkholderia cepacia complex as a cause of community acquired bacteremia in a young immuncompetent male.

Burkholderia cepacia complex (BCC) is a well-recognized cause of nosocomial infections. We describe here a young healthy male who presented with fever and chest pain with ECG changes of acute pericarditis. Two sets of blood cultures at separate timings grew gram negative bacilli identified as BCC by molecular methods. The patient responded to intravenous ceftazidime despite high ceftazidime MIC's. The source of infection was probably contaminated nasal spray/nasal saline wash which he used after a balloon sinoplasty procedure one month ago. Issues related to accurate identification and susceptibility testing of BCC are also discussed.

The outcome of treating ESBL infections with carbapenems vs. non carbapenem antimicrobials.

BACKGROUND: In India where the prevalence of extended spectrum beta lactamase (ESBL) producing organisms among gram negative organisms is 60-70% and Ertapenem was unavailable at the beginning of this study, exclusive use of Group 2 Carbapenems (Imipenem and Meropenem) for treatment raises issues of cost and development of resistance. Therefore the role of non-Carbapenem alternatives, chiefly Betalactam + Betalactamase inhibitors (BL-BLI) was explored in this prospective observational study at a private tertiary care teaching hospital. PATIENTS AND METHODS: 522 consecutive in door patients from the period between June 2006 to March 2007and June 2008 to December 2008, who had true infections with ESBL producing organisms were enrolled in the study. Antimicrobials were prescribed or changed by the treating physicians on the basis of the nature and severity of infection, the susceptibility of the organism and the affordability of the patient. Patients who received a Carbapenem at any time during treatment were considered in the Carbapenem group. Those who never received a Carbapenem at any time during treatment were considered in the non-Carbapenem group. RESULTS: Of the 522 infections, 287 were urinary tract infections, 60 were skin structure infections, 60 were bacteremias, 55 were hospital acquired pneumonias, 31 were intra-abdominal infections and 29 were other infections. There were 351 E. coli, 119 K. pneumoniae, 23 K. oxytoca, 16 Enterobacter aerogenes, 5 Kozoanae, 4 Enterobacter agglomerans, 3 Citrobacter freundi, 1 E. cloacae, 1 Enterobacterspp. and 1 Morgenella morganii isolates. Clinical outcomes were available for 486 patients. 339 patients who were in the non-Carbapenem group and who might have had less serious infections had a clinical success rate of 79.6%. 147 patients who were in the Carbapenem group and who might have had more serious infections had a clinical success rate of 85.71%. CONCLUSIONS: It is possible to successfully treat at least the less serious infections due to ESBL producing gram negative organisms with non-Carbapenem antimicrobials. This will not compromise outcomes but will likely result in restricting the use of Carbapenems which may help preserve their efficacy against increasingly resistant organisms.

Antimicrobial Resistance: The 'Other' Pandemic! : Based on 9th Dr. I. C. Verma Excellence Award for Young Pediatricians Delivered as Oration on 19th Sept. 2021.

Antimicrobial resistance is projected to kill 10 million people by 2050. The biggest driver of antimicrobial resistance is excessive/unrestricted use of antimicrobials in humans and animals. Antimicrobial resistance is a problem in all types of pathogens including bacteria, mycobacteria, viruses, fungi, and parasites both globally and India and in both adults and children. The areas of greatest concern for India is the epidemic of MDR and XDR tuberculosis and resistance in gram-negative pathogens. The alarming rate of extended spectrum beta lactamase (ESBL) production in Enterobacteriales in both community and health care-associated infections is driving carbapenem use. Rates of carbapenem resistance are now significantly high in health care-associated gram negative pathogens with associated high mortality rates. The key solution to this antimicrobial resistance crisis needs participation of all stakeholders and lies in promoting rational antimicrobial therapy.

The Emergence of Omicron: Challenging Times Are Here Again!

COVID-19 has been reported to have caused more than 286 million cases and 5.4 million deaths till date. COVID variants have appeared at regular intervals-alpha, beta, gamma, delta and now omicron. 'Omicron' is driving the current surge of cases in most countries including India and is poised to replace 'delta' the world over. This variant with more than 50 mutations is phylogenetically very different from other variants. The omicron variant spreads rapidly with an average doubling time of two days. The disease so far has been mild as compared with delta. Though previous infection and vaccination offer little or no protection against infection with omicron, they do seem to partially protect against hospitalization and severe disease. Booster vaccinations have not made any notable impact on the spread of omicron and have further worsened global vaccine equity. The indirect consequences of omicron from lockdowns, restrictions, travel bans, economic losses, health care worker infections and overwhelming of health care facilities are likely to be enormous. The direct effects of omicron on children are expected to be mild like with the previous variants. However, the indirect effects on child mental, physical, and social health may be considerable owing to school closures, missed vaccinations, neglect of other diseases, etc. It is, therefore, imperative that governments take rational decisions to navigate the world through this latest crisis.

Monkeypox: A Review.

Monkeypox is caused by a pox virus closely related to smallpox virus and spreads from animals to humans, and humans to humans following close contact. Prior smallpox vaccination gives partial protection against monkeypox. The steady increase in monkeypox cases in Africa over the past few decades were ignored by the global scientific community till this year, when more than 16,000 cases have been reported from nonendemic countries. Monkeypox has recently been labelled as a public health emergency of international concern by the WHO. While most of the current cases are in men who have sex with men, there is the larger threat of the disease spilling into the general population. The disease is characterized by a short febrile illness with lymphadenopathy followed by a rash which spreads centrifugally and passes through phases of macules, papules, vesicles, and pustules. Recovery occurs in most patients within 2-4 wk. Complications are more likely in children, pregnant women, and the immunocompromised. Specific diagnosis is by detection of viral DNA by PCR. Treatment is largely symptomatic. Tecorivimat is a promising antiviral drug. Vaccination with the currently available smallpox vaccines is recommended for high-risk groups, health care workers, and close contacts. Control of the monkeypox outbreak needs a multipronged effort comprising enhanced surveillance, quick diagnosis, isolation of affected people, ring immunization, and adoption of "one health" approach.

The mystery behind a 1000 day fever in a young male.

This case is of a 23 year old diabetic male who presented with fever and splenic lesions. He continued to have fever off and on over the next 3 years despite empirical antibiotics and anti-tubercular therapy. No definitive diagnosis could be made despite exhaustive investigations. Finally, a splenectomy resulted in sustained defervescence. The splenic histopathology showed caseating granulomas but aerobic cultures, Xpert MTB/Rif ULTRA, TB and fungal cultures were negative. A final diagnosis of splenic melioidosis was made based on the clinical features, radiology, histopathology, literature review and absence of an alternative diagnosis.

Treatment of MRSA infections in India: Clinical insights from a Delphi analysis.

PURPOSE: International and Indian guidelines for the management of patients with methicillin-resistant Staphylococcus aureus (MRSA) infections are available, but the local guidelines are not MRSA-specific. This study aimed to provide clinical insights for the treatment of MRSA infections in India. METHODS: We used a three-step modified Delphi method to obtain insights. Ten experts comprising infectious disease specialists, microbiologists, pulmonologists, and critical care experts agreed to participate in the analysis. In round 1, a total of 161 statements were circulated to the panel and the experts were asked to 'agree' or 'disagree' by responding 'yes' or 'no' to each statement and provide comments. The same process was used for 73 statements in round 2. Direct interaction with the experts was carried out in round 3 wherein 35 statements were discussed. At least 80% of the experts had to agree for a statement to reach concordance. RESULTS: Eighty-eight statements in round 1, thirty-eight statements in round 2, and eight statements in round 3 reached concordance and were accepted without modification. The final document comprised 152 statements on the management of various syndromes associated with MRSA such as skin and soft tissue infections, bacteremia and endocarditis, pneumonia, bone and joint infections, and central nervous system infections. CONCLUSIONS: This analysis will assist clinicians in India to choose an appropriate course of action for MRSA infections.

Definition, diagnosis, and management of COVID-19-associated pulmonary mucormycosis: Delphi consensus statement from the Fungal Infection Study Forum and Academy of Pulmonary Sciences, India.

COVID-19-associated pulmonary mucormycosis (CAPM) remains an underdiagnosed entity. Using a modified Delphi method, we have formulated a consensus statement for the diagnosis and management of CAPM. We selected 26 experts from various disciplines who are involved in managing CAPM. Three rounds of the Delphi process were held to reach consensus (≥70% agreement or disagreement) or dissensus. A consensus was achieved for 84 of the 89 statements. Pulmonary mucormycosis occurring within 3 months of COVID-19 diagnosis was labelled CAPM and classified further as proven, probable, and possible. We recommend flexible bronchoscopy to enable early diagnosis. The experts proposed definitions to categorise dual infections with aspergillosis and mucormycosis in patients with COVID-19. We recommend liposomal amphotericin B (5 mg/kg per day) and early surgery as central to the management of mucormycosis in patients with COVID-19. We recommend response assessment at 4-6 weeks using clinical and imaging parameters. Posaconazole or isavuconazole was recommended as maintenance therapy following initial response, but no consensus was reached for the duration of treatment. In patients with stable or progressive disease, the experts recommended salvage therapy with posaconazole or isavuconazole. CAPM is a rare but under-reported complication of COVID-19. Although we have proposed recommendations for defining, diagnosing, and managing CAPM, more extensive research is required.