FULL ISSUE Vol 56, No 4; Oct.- Dec., 2020

Published online: 2020-12-31

THIEME Editorial 189

Editorial Nobel Prize in Medicine 2020: Acknowledging the Discovery of Hepatitis C Virus

Arka De1 Yogesh K. Chawla2

1Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, Punjab, India Yogesh K. Chawla 2Kalinga Institute of Medical Sciences, Bhubaneshwar, Odisha, India

Ann Natl Acad Med Sci (India):2020;56:189–190

The lack of motivation for research among young doctors has Molecular techniques were at its often been blamed to the suboptimal standards of medical nascency and the adoption of this research in general in India. The Nobel Prize in Medicine approach by Michael Houghton and (Physiology) in 2020 has aroused great interest among doc- his team at Chiron Corp., California, tors as it was awarded for the discovery of the hepatitis C United States, ultimately led to the Arka De virus (HCV)—a virus with substantial clinical significance. identification of the virus. The team The painstaking and thorough research of the three Nobel at Chiron collaborated with Daniel Bradley of the Center of laureates (Harvey J. Alter, Michael Houghton, and Charles Disease Control and Prevention (CDC), Atlanta, United States, M. Rice) ultimately paved the way for HCV from being an and developed a library of complementary deoxyribonu- unknown entity to a curable viral infection in a short span cleic acid (cDNA) using samples obtained from chimpan- of five decades. Their work revolutionized the fields of virol- zees infected with non-A non-B hepatitis. These were then ogy, immunology, and hepatology.1 The road to the discovery transferred to bacteria and cloned using bacteriophages. The of the virus is a remarkable story of the triumph of pas- premise was that some of the proteins encoded by these sion, perseverance, and multifaceted, meticulous research. cDNA would react with antibodies present in patients and

Acknowledgment of the discovery of the virus by the Noble chimpanzees infected with non-A non-B hepatitis. After Committee should encourage and motivate young doctors for years of painstaking research, the first such antigen epitope going into research in their respective fields. (corresponding to the viral envelope) was identified in 1989 The journey into our understanding of HCV started almost from a clone called 5–1-1.6,7 This newly identified virus with five decades back in 1974 after the discovery of hepatitis A a positive stranded ribonucleic acid (RNA) was named hep- and hepatitis B in the preceding two decades.2 Harvey J. Alter atitis C and was subsequently classified as a Flavivirus. The and his team working at the Department of Blood Transfusion novel methods adopted by Houghton drastically changed the in the Bethesda center of National Institutes of Health, United field of virology and heralded a molecular revolution with States, noted that a substantial number of cases of posttrans- the rapid identification of other viruses like hepatitis G in the fusion hepatitis was not attributable to either hepatitis A or subsequent years. hepatitis B. Further, they demonstrated that this non-A non-B By the beginning of the 1990s, researchers had discovered hepatitis could be transmitted to chimpanzees.3-5 Their find- the modes of transmission of HCV, established its infectiv- ings were corroborated by other teams and this transmissi- ity in chimpanzees, and unraveled its nuclear structure. bility of disease pointed toward an infective agent. However, However, whether infection with the virus alone was suffi- hopes of a rapid identification of the infective agent proved cient to cause clinically significant disease was yet unknown. futile over the next 15 years and the virus eluded detection The answer to this question came from the seminal work of by the traditional techniques of microscopy, cell culture, and Charles M. Rice and his team at Washington University, USA. serology. They constructed a library of cDNA clones consisting of the

Address for correspondence DOI https://doi.org/ © 2020. National Academy of Medical Sciences (India). Yogesh K. Chawla, MD, DM, FAMS, 10.1055/s-0040-1722381 This is an open access article published by Thieme under the terms of the Creative Kalinga Institute of Medical Sciences, ISSN 0379-038X. Commons Attribution-NonDerivative-NonCommercial-License, permitting copying Bhubaneshwar 751024, Odisha, and reproduction so long as the original work is given appropriate credit. Contents India (e-mail: [email protected]). may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/). Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India 190 Editorial

3′ untranslated region of the HCV genome and a consensus different yet related disciplines of medical research, namely sequence. RNA transcribed from these cDNA clones was infec- clinical and epidemiological research, molecular biology, and tive to chimpanzees and resulted in hepatitis. Thus, the link virology. Passion, perseverance, and the spirit to accept fail- between HCV and liver disease was firmly established.8,9 In ures are paramount for success in research. As discussed, the the new millennium, further granular understanding of viral decade between the realization that non-A non-B hepatitis biology including its life cycle was facilitated by the devel- is caused by a transmissible agent and the identification of opment of cell culture systems and the identification of a this agent as a novel virus was riddled with repeated failures. viral isolate that could infect human hepatoma cell lines. Lastly, the ability to draw logical conclusions is undeniably The construction of subgenomic viral replicons greatly aided the most valued quality in a researcher. the design and screening of targeted directly acting drugs. The HCV success story is a testament to the remarkable Indeed, research into HCV has now come full cycle with the potential of human endeavor. Indeed, from being a disease advent of highly effective directly acting antivirals (DAAs) about which nothing was known until approximately five that can cure HCV in the vast majority of the patients. decades ago, the revolutionary work of these stalwarts has Chronic HCV infection is among the predominant causes paved the way to easy diagnosis and treatment which is now of cirrhosis and hepatocellular carcinoma and accounts for making us think about the possibility of eliminating HCV significant morbidity and mortality. The grim implications by 2030. of a diagnosis of HCV can be construed from the fact that Conflict of Interest it is colloquially referred to as “kala piliya” (black or death None declared. jaundice) in North India. The World Health Organization estimates that globally there are 71 million people with chronic HCV infection. The viral prevalence in India is esti- References mated to be 0.5 to 1% with regions of higher prevalences in 1 Press release: the Nobel prize in physiology or medicine 10 the North East and Punjab. Fundamental research in HCV 2020 [Internet]. Nobel Media AB; 2020. Available at: https:// has had far reaching impacts in clinical practice. Knowledge www.nobelprize.org/prizes/medicine/2020/summary/. of the modes of viral transmission and the development of Accessed November 29, 2020 methods for diagnostic methods led to the adoption of a 2 Baumert TF. The Nobel Prize in Medicine 2020 for the policy of universal screening of blood donors which has led Discovery of Hepatitis C Virus: transforming hepatology. J Hepatol 2020;73(6):1303–1305 to a significant decrease in blood-borne viral transmission. 3 Alter HJ, Holland PV, Purcell RH, et al. Posttransfusion hepatitis Doctors and health care workers are well aware of the utility after exclusion of commercial and hepatitis-B antigen-positive of universal safety precautions. Treatment of HCV had long donors. Ann Intern Med 1972;77(5):691–699 been an unmet need. Treatment failures were frequent in the 4 Feinstone SM, Kapikian AZ, Purcell RH, Alter HJ, Holland PV. interferon era and adverse effects were common. Oral DAAs Transfusion-associated hepatitis not due to viral hepatitis type A or B. N Engl J Med 1975;292(15):767–770 have revolutionized the management of HCV and is offering 5 Alter HJ, Purcell RH, Holland PV, Popper H. Transmissible agent the hope of cure to millions of patients. The availability of in non-A, non-B hepatitis. Lancet 1978;1(8062) :459–463 pan-genotypic regimens precludes the need for pretreatment 6 Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, genotype testing, facilities for which are not widely available Houghton M. Isolation of a cDNA clone derived from in resource-limited settings like India. Treatment of chronic a blood-borne non-A, non-B viral hepatitis genome. HCV without prior genotype testing using pan-genotypic Science 1989;244(4902) :359–362 7 Kuo G, Choo QL, Alter HJ, et al. An assay for circulating antibod- regimens has been shown to be effective and logistically fea- ies to a major etiologic virus of human non-A, non-B hepatitis. sible in Punjab under a program funded by the Mukh-Mantri Science 1989;244(4902) :362–364 11 Punjab Hepatitis C Relief Fund. This approach has now been 8 Kolykhalov AA, Feinstone SM, Rice CM. Identification of a endorsed by international authorities and has been extended highly conserved sequence element at the 3′ terminus of hep- to the whole of India under the National Viral Hepatitis atitis C virus genome RNA. J Virol 1996;70(6):3363–3371 Control Program. 9 Kolykhalov AA, Agapov EV, Blight KJ, Mihalik K, Feinstone SM, Rice CM. Transmission of hepatitis C by intrahepatic inocula- The journey into the discovery of HCV holds several key tion with transcribed RNA. Science 1997;277(5325) :570–574 lessons for any budding researcher. Identification of the prob- 10 Goel A, Seguy N, Aggarwal R. Burden of hepatitis C virus lem is the first step in finding the solution. Indeed, recogni- infection in India: a systematic review and meta-analysis. tion of the problem of non-A non-B hepatitis by Alter was J Gastroenterol Hepatol 2019;34(2):321–329 the first step in the road to the discovery of HCV. Teamwork 11 Dhiman RK, Grover GS, Premkumar M, et al; MMPHCRF and a multifaceted, multidisciplinary approach is funda- Investigators. Decentralized care with generic direct-acting antivirals in the management of chronic hepatitis C in a public mental for delving deep into any problem. Professionally, health care setting. J Hepatol 2019;71(6):1076–1085 Alter, Houghton, and Rice belonged to three fundamentally

THIEME Review Article 191

Neurological Problems in COVID-19 Pandemic

Shiv Kumar Saini1 Kuljeet Singh Anand1 Abhishek Juneja1 Rakesh Kumar Mahajan2

1Department of Neurology, Dr Ram Manohar Lohia Hospital, Address for correspondence Kuljeet Singh Anand, DM, Department New Delhi, India of Neurology, Dr Ram Manohar Lohia Hospital, New Delhi 110001, 2Department of Microbiology, Dr Ram Manohar Lohia Hospital, India (e-mail: [email protected]). New Delhi, India

Ann Natl Acad Med Sci (India):2020;56:191–196

Abstract Coronavirus disease 2019 (COVID-19) is a potentially severe acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This outbreak, which emerged in Wuhan city, rapidly spread throughout China and has now become a global public health concern. SARS-CoV-2 is a highly pathogenic and transmissible virus. Common clinical manifestations of COVID-19 include fever, dry cough, shortness of breath, muscle ache, headache, and confusion. Currently, there is no confirmed effective therapeutic strategy for COVID-19 because the pathological mechanism is poorly understood. In addition to the respiratory system involvement, recent evidence has shown that SARS-CoV-2 can affect other organ systems including nervous, vascular, digestive, and urinary system. Various neurological complications have also been described in various studies. Nervous system involvement in the case of SARS-CoV-2 is explained by direct neuro invasion, immune mechanism, and other systemic factors. Neurological complications due to SARS-CoV-2 include both central and peripheral nervous system involvement. Central nervous system complications

Keywords range from mild headache to seizures, encephalitis, myelitis, and acute cerebrovascular ►►neurological accidents. Peripheral nervous system complications range from vague muscle pains ►►pandemic to Guillain–Barré syndrome. This article briefly discusses the various neurological and ►►COVID-19 mental health issues related to COVID-19.

Introduction respiratory syndrome (MERS-CoV, 2013–2014). SARS-Cov-2 shares 88% genetic similarity with SARS-CoV and 50% Coronavirus disease 2019 (COVID-19) is a potentially severe resemblance with MERS-CoV.3 acute respiratory infection caused by severe acute respiratory Clinical manifestations of COVID-19 are fever 83%, syndrome coronavirus 2 (SARS-CoV-2). This outbreak, which cough 82%, shortness of breath 31%, muscle ache 11%, confu- emerged in Wuhan city, rapidly spread throughout China and sion 9%, headache 8%, and sore throat 5%.4 SARS-CoV-2 is highly has now become a global public health concern. As of May pathogenic and transmissible virus.5 Currently, there is no con- 21, 2020, globally 48,93,186 cases of COVID-19 have been firmed effective therapeutic strategy for COVID-19 because the 1 reported, including 3,23,256 deaths. pathological mechanism is poorly understood. In addition to The SARS-CoV-2 is from the family of large enveloped non- the respiratory system involvement, recent evidence has shown 2 segmented positive-sense ribonucleic acid viruses. SARS-CoV that SARS-CoV-2 can affect other organ systems including is a respiratory virus, which mutates quickly and causes nervous, vascular, digestive, urinary, and hematological.4,6 The common cold to severe diseases such as severe acute respi- pathological findings established the nature of multiorgan ratory syndrome (SARS-CoV, 2002–2004) and Middle East

DOI https://doi.org/ © 2020. National Academy of Medical Sciences (India). 10.1055/s-0040-1717833 This is an open access article published by Thieme under the terms of the Creative ISSN 0379-038X. Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/). Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India 192 Neurological Problems in COVID-19 Pandemic Saini et al.

damage by SARS-CoV-2, which consists of pulmonary lesion Digestive Tract Route and cerebral edema, microvascular steatosis, and thrombo- ACE2 receptors are expressed in intestinal epithelial cells also sis.7 Various neurological complications were also described in besides alveolar epithelial cells.5 The intestinal viral infection various studies from different regions of the world. causes inflammatory reaction damaging the mucosal barrier, Neuropathogenesis: Nervous system involvement in case gaining entry into the blood circulation.5,27 There is a possi- of SARS-CoV-2 is explained by direct neuroinvasion, immune bility of retrograde viral entry into the CNS through enteric mechanism, and other systemic factors (hypoxia, thrombosis, nervous system.5 metabolic derangements). Lymphatics and/or Cerebrospinal Fluid Route The virus may gain entry into the CNS through lymphatic Direct Neuroinvasion Nervous System Route pathway. It is capable of invading the hilar and mesenteric lymph nodes directly, ultimately entering the blood stream SARS-CoV-2 is in the same beta-coronavirus clade as and thus spreading to the CNS.28,29 MERS-CoV and SARS-CoV, and shares highly homologi- cal sequence with SARS-CoV that has been revealed in the Immune Mechanism genomic analysis.8 The evidence shows that COVID-19 shares SARS and COVID-19 have led to a large number of mortali- similar pathogenesis and receptors for the entry of SARS- ties, most of which have been due to multiple organ failure CoV-2 into human host cells as SARS-CoV.9-11 Most CoVs share triggered by virus induced systemic inflammatory response a similar viral structure and infection pathway and thus the syndrome. 30,31 The ability of the virus to infect macrophages, infection mechanisms earlier found for other CoVs may also microglia, and astrocytes in the CNS is principally import- be applicable for SARS-CoV-2.12,13 ant. Interleukin-6 has been correlated with the severity of The animal and human experimental studies confirmed COVID-19 symptoms.32 that either SARS-CoV or MERS-CoV was capable to infect the brain.14 Additionally, in one report the SARS-CoV Miscellaneous was detected in the cerebrospinal fluid (CSF) of a patient The virus causes diffuse alveolar and interstitial inflamma- with neurological consequence following SARS infec- tory reaction in the lungs causing poor alveolar gas exchange. tion.15 The evidence of angiotensin-converting enzyme 2 This in turn may lead to hypoxic damage in the central ner- (ACE2) expression by the glial cells and neurons in the brain vous tissue.33,34 further suggests neurotropism of the SARS-CoV-2.16-20 SARS-CoV-2 infection is associated with a prothrombotic The main transmission of CoV is through droplet spread; state producing venous and arterial thromboembolism and CoV-laden droplets sticking to the nasal mucosa travel to elevated D-dimer levels.35 Severe COVID-19 is linked with the lungs and also possibly enter central nervous system proinflammatory cytokines that induce endothelial and (CNS) through the olfactory nerve endings.5 This hypoth- mononuclear cell activation with expression of tissue factor, esis of CNS invasion through the olfactory nerve endings leading to coagulation activation and thrombin generation could also explain the symptom of hyposmia in infected and thrombotic tendencies causing ischemic and thrombotic patients.21,22 episodes. It has been proposed that COVID-19 might stim- Hypogeusia triggered by SARS-COV-2 infection could ulate the production of antiphospholipid antibodies as a result from injury to any of the three cranial nerves—facial, mechanism of ischemic stroke.36 glossopharyngeal nerve, and vagus nerve, which carry the The biological characteristics of the CNS may enable exac- sense of taste to the nucleus of the solitary tract or tha- erbation of the neurological damage caused by CoV infec- lamic nuclei.5 There lies a possibility of SARS-CoV-2 reaching tions. The CNS has a dense parenchymal structure and the the respiratory center from nucleus of the solitary tract typical absence of permeability of its blood vessels is a bar- due to close proximity, thus causing neurogenic refractory rier to virus invasion. Nevertheless, if a virus gains access dyspnea.20,23 to the CNS, it is hard to eliminate.37 Due to the absence of major histocompatibility complex antigens in nerve cells, the Hematogenous Route removal of viruses in nerve cells depends exclusively on the SARS-CoV-2 fixes to the ACE2 receptor on the alveolar epi- role of cytotoxic T cells.38 thelial cells, triggering endothelial damage and entering the blood circulation.5 The virus not only infects the epi- Neurological Manifestations thelial cells but also the resident, infiltrating and circulat- SARS-CoV-2 is mainly respiratory virus but various neurolog- ing immune cells that secrete cytokines and these infected ical manifestations and complications have been described in circulating immune cells transport the virus to other literature. Although there are plenty of studies and articles organs and may intensify the permeability of the blood– available on clinical features of COVID-19, dedicated studies brain barrier, thereby encouraging the virus to enter the on neurological manifestations are scarce. Available litera- 24 brain and causing viral encephalitis. Although there is ture is summarized in ►Table 1. rare evidence that CoV, especially SARS CoV-2, invades the Mao et al studied 214 patients of COVID-19 from China nervous system via the blood circulation pathway, subse- and of these, 78 (36.4%) had various neurologic manifesta- 25,26 quent studies are expected. tions. Seventy-eight patients (36.4%) had nervous system

Annals of the National Academy of Medical Sciences (India) Vol. 56 No. 4/2020 ©2020. National Academy of Medical Sciences (India). Neurological Problems in COVID-19 Pandemic Saini et al. 193 manifestations: CNS (53 [24.8%]), peripheral nervous system ischemic stroke and one patient had a subacute ischemic (PNS) (19 [8.9%]), and skeletal muscle injury (23 [10.7%]). In stroke.40 CNS manifestations, the most common symptoms were diz- Li et al studied 221 consecutive hospitalized patients with ziness (36 [16.8%]) and headache (28 [13.1%]). In patients COVID-19 infection. They found that 11 (5%) patients devel- with PNS involvement, the common symptoms were taste oped acute ischemic stroke, one (0.5%) developed cerebral impairment (12 [5.6%]) and smell impairment (11 [5.1%]).39 venous sinus thrombosis, and one (0.5%) developed intrace- The patients with severe infection were relatively older (58.2 rebral hemorrhage. The mean age of patients who developed vs. 48.9 years) and had underlying disorders particularly hyper- stroke (72 years) was higher (52 years). Of the 11 patients tension (36.4 vs. 15.1%), and lack of typical clinical symptoms with ischemic stroke, five were associated with large artery such as fever (45.5 vs. 73%) and dry cough (34.1 vs. 61.1%).39 disease, three with small artery disease, and other three with Furthermore, nervous system manifestations were sig- cardioembolic events. The fibrin D-dimer levels were 12-fold nificantly more common in severe infections compared with higher in patients who developed stroke demonstrating a nonsevere infections (45.5 vs 30.2%).39 hypercoagulable state.41 Helms et al described the neurologic features in an obser- Yang et al did a retrospective, observational study vational series of 58 of 64 consecutive patients admitted to and enrolled 52 critically ill adult patients with SARS- intensive care unit (ICU) due to acute respiratory distress CoV-2 pneumonia who were admitted to the ICU in Wuhan, syndrome following SARS-CoV-2 infection. Neurological China, and found headache in 6% of the patients.42 complications were seen in 49/58 (84%) patients. As evaluated by confusion assessment method for ICU scale, Central Nervous System agitation was the most common symptom 40/58 (69%) followed by confusion 26/40 (65%). Diffuse corticospinal Cerebrovascular Accidents tract signs with exaggerated tendon reflexes and bilateral Mao et al described six cases of cerebrovascular accident extensor plantar reflexes were seen in 39 patients (67%). Of (CVA) in their cohort of 214 patients. There were five cases the patients who had been discharged, 15 of 45 (33%) had of ischemic and one case of hemorrhagic stroke.39 The French dysexecutive syndrome consisting of inattention, disorien- cohort had three cases of ischemic strokes that were detected tation, or poorly organized movements in response to com- on neuroimaging when the patients undertook imaging for mand. Two asymptomatic patients each had a small acute encephalopathy.40 In a study by Li et al., the incidence of

Table 1 Neurological manifestations in COVID-19 as described in various studies S.N. Authors/year Study population Neurological manifestations 1. Mao et al39 214 admitted patients (China) CNS involvement (24.8%) Dizziness: 16.8% (2020) Headache: 13.1% Impaired consciousness: 7.5% Acute CVA: 2.8% Ataxia: 0.5% Seizure: 0.5% PNS involvement (8.9%) Taste impairment: 5.6% Smell impairment: 5.1% Vision impairment: 1.4% Nerve pain: 2.3% Skeletal muscular Muscle pain manifestations (10.7%) 2 Helms et al40 Case series of 58 patients Agitation in 69%, confusion in 65%, corticospinal tract signs (2020) (France) in 67%, dysexecutive syndrome in 36% 3 Li et al41 Case series of 221 admitted Acute ischemic stroke in 5%, cerebral venous sinus thrombosis (2020) Patients (China) in 0.5%, cerebral hemorrhage in 0.5% 4 Yang et al42 52 critically ill adult patients Headache in 6% (2020) (China) 5 Wang et al43 Case series of 138 hospitalized Dizziness in 9%; headache in 7% (2020) patients (China) 6 Toscano et al56 Case series of 5 patients (Italy) Flaccid areflexic limb weakness in 80%, facial weakness in 60% (2020) 7 Lechien et al59 417 patients (Belgium, France, Smell dysfunction in 86%, taste dysfunction in 82% (2020) Italy, Spain, and Switzerland)

stroke in COVID-19 patients was ~5% and they postulated Sarma and Bilello reported a case of 28-year-old female elevated levels of C-reactive protein and D-dimer, indicative who tested positive for COVID-19 via RT-PCR of nasopharyn- of an inflammatory state and irregularities with the coagu- geal swab and later on diagnosed as longitudinally extensive lation cascade, respectively, which might play a part in the acute transverse myelitis.49 pathophysiology of stroke in COVID-19 infection.41 Sharifi-Razavi et al described a case of intracranial bleed- Encephalopathy ing ensuing in CVA in a 79-year-old COVID-19-positive male Chen et al in a retrospective study of the clinical charac- who was neither a known hypertensive nor on any antico- teristics of 113 COVID-19 patients from China documented agulants that could have caused this event.44 The authors hypoxic encephalopathy in 20 patients.50 The incidence was postulated that probably dysregulation in the ACE2 receptors significantly lower in the patients who had recovered. Mao leading to cerebral autoregulation disruption and high blood et al described impaired consciousness in 16 (7.5%) patients pressure spikes resulted in arterial wall rupture. in their cohort but the diagnostic criteria used were not well-defined.39 Filatov et al reported a case of a 74-year-old Encephalitis male with multiple comorbidities who developed altered Moriguchi et al described first confirmed case of mental status after headache, fever, and cough.51 COVID-19-related viral encephalitis from Japan.45 A 24-year- old man presented with headache and fever followed by sei- Seizures zure and episode of unconsciousness. He had neck stiffness; computed tomographic (CT) scan of brain was unremarkable. Vollono et al described a case of 78-year-old SARS-CoV-2-positive Cerebrospinal fluid reverse transcription-polymerase chain female patient, who was admitted for focal status epilepti- reaction (CSF RT-PCR) detected SARS-CoV-2. Brain mag- cus without any prodromal symptoms in the form of myoc- netic resonance imaging (MRI) revealed diffusion restriction lonic jerks of the right side of face and right-sided limbs.52 The along the wall of inferior horn of right lateral ventricle, and electroencephalogram discovered semirhythmic, irregular, fluid-attenuated inversion recovery images showed hyperin- high amplitude delta activity, mainly lateralized over the left tense signal changes in the right mesial temporal lobe and fronto-centro-temporal regions, consistent with focal status hippocampus suggestive of encephalitis.45 epilepticus. Huang et al reported a case of 40-year-old woman from Sohal and Mansur also reported a case of 72-year-old United States who presented with fever followed by syncope man with comorbidities, who was noted to have multiple

and nasopharyngeal swab on admission was positive for episodes of tonic clonic movements of his upper and lower SARS-CoV-2 and afterward CSF was found to be positive for extremities.53 SARS-CoV-2 as well.46 Headache and Dizziness Acute Hemorrhagic Necrotizing Encephalopathy Poyiadji et al described a case of a female patient in her late Headache and dizziness have been reported as minor symp- fifties, presenting with a 3-day history of cough, fever, and toms associated with presentation of COVID-19 in different altered mental status and subsequently the diagnosis of studies. The incidence of headache ranges from 6 to 13.1% COVID-19 made by RT-PCR of nasopharyngeal swab speci- and dizziness from 9 to 16.8% but the detailed mechanism men.47 In this case, testing for the presence of SARS-CoV-2 in and pathogenesis have not been discussed.39,42,43 the CSF was not done. Noncontrast head CT images demonstrated symmetric hypoattenuation within bilateral medial Peripheral Nervous System thalami with a normal CT angiogram and CT venogram. Brain MRI demonstrated hemorrhagic rim enhancing lesions Olfactory and Gustatory Impairment within the bilateral thalami, medial temporal lobes, and sub- Mao et al reported occurrence of taste impairment (12 insular regions. Authors suggested this patient might have [5.6%]) and smell impairment (11 [5.1%]) in their 214 patients a cytokine storm syndrome due to severe COVID-19 that cohort.39 Bagheri et al described that anosmia and hyposmia resulted in blood–brain barrier breakdown leading to this were seen in 48.23% of the respondents, while 83.38% also presentation. had a decreased taste sensation.54

Acute Myelitis Guillain–Barré Syndrome Zhao et al described a case of 66-year-old male form Wuhan Many cases of Guillain–Barré syndrome (GBS) are now city, China, who was admitted for fever and fatigue of 2 days reported that are related to COVID-19. Zhao et al reported a without cough; later on he developed acute flaccid parapare- case of 61-year-old Chinese female patient who presented sis with sensory level at T-10 and urinary and bowel incon- with acute weakness in both legs and severe fatigue. The tinence.48 All other microbiological studies were negative diagnosis of GBS was made on the basis of clinical exam- except for SARS-CoV-2 nucleic acid testing in nasopharyngeal ination and electrophysiological studies. She was treated swab. Authors suggested clinical findings could be ascribed with intravenous immunoglobulin. A week following this, to a postinfectious acute myelitis.48 patient developed dry cough and fever; oropharyngeal

Annals of the National Academy of Medical Sciences (India) Vol. 56 No. 4/2020 ©2020. National Academy of Medical Sciences (India). Neurological Problems in COVID-19 Pandemic Saini et al. 195 swab detected SARS-CoV-2 on RT-PCR assay. Hence, GBS 4 Chen N, Zhou M, Dong X, et al. Epidemiological and clinical charac- related to SARS-CoV-2 might follow the pattern of a para- teristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, infectious profile, instead of the classic postinfectious China: a descriptive study. Lancet 2020;395(10223):507–513 5 Li Z, Liu T, Yang N, et al. Neurological manifestations of patients profile.55 with COVID-19: potential routes of SARS-CoV-2 neuroinva- Toscano et al reported five patients of GBS with COVID-19. sion from the periphery to the brain. Front Med 2020. Doi: The first symptoms of GBS were lower-limb weakness and 10.1007/s11684-020-0786-5 paresthesia in four patients and facial diplegia followed by 6 Huang C, Wang Y, Li X, et al. Clinical features of patients ataxia and paresthesia in one patient. After examination and infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395(10223):497–506 proper investigation (nerve conduction and CSF studies), GBS 7 Xu Z, Shi L, Wang Y, et al. Pathological findings of 56 was diagnosed and treated accordingly. COVID-19 associated with acute respiratory distress syn- Overall, these case reports only propose a likely associa- drome. Lancet Respir Med 2020;8(4):420–422 tion between GBS and SARS-CoV-2 infection, and more cases 8 Yu F, Du L, Ojcius DM, Pan C, Jiang S. Measures for diagnosing with epidemiological data are needed to support a causal and treating infections by a novel coronavirus responsible for relationship. a pneumonia outbreak originating in Wuhan, China. Microbes Infect 2020;22(2):74–79 9 Song Z, Xu Y, Bao L, et al. From SARS to MERS, thrusting coro- Skeletal Muscle Damage naviruses into the spotlight. Viruses 2019;11(1):59 10 Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemi- Mao et al reported skeletal muscle injury in 23 of their ology of 2019 novel coronavirus: implications for virus origins patients that is 10.7% of cohort.39 Compared with the patients and receptor binding. Lancet 2020;395(10224) :565–574 without muscle injury, patients with muscle injury had sig- 11 Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by the novel coronavirus from Wuhan: an analysis based nificantly higher levels of creatine kinase (median, 400.0 U/L on decade-long structural studies of SARS coronavirus. J vs. median, 58.5 U/L), irrespective of their severity. They have Virol 2020;94(7):e00127–e20 seen that patients with muscle injury had higher neutrophil 12 Yuan Y, Cao D, Zhang Y, et al. Cryo-EM structures of MERS-CoV counts, lower lymphocyte counts, higher C-reactive protein and SARS-CoV spike glycoproteins reveal the dynamic recep- levels, and higher D-dimer levels. tor binding domains. Nat Commun 2017;8:15092 13 Hulswit RJ, de Haan CA, Bosch BJ. Coronavirus spike protein and tropism changes. Adv Virus Res 2016;96:29–57 Other Manifestations 14 Paybast S, Emami A, Koosha M, Baghalha F. Novel coronavirus disease (COVID-19) and central nervous system com-

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THIEME Review Article 197

COVID-19 Management in India: Medical Aspects, Current Concepts, and Evolving Directions

Daya K. Hazra1 Padmamalika K. Neehazra1 Suratwant Hazra1 Adarsh N. Segal1

1Department of Medicine, Boston Medical Centre, Agra, Address for correspondence Daya K. Hazra, MD, FAMS, PhD, MSc, Uttar Pradesh, India Boston Medical Centre, Swamibagh, Agra, Uttar Pradesh 282005, India (e-mail: [email protected]).

Ann Natl Acad Med Sci (India):2020;56:197–207

Abstract This review deals with the emerging coronavirus disease 2019 (COVID-19) epidemic summarizing current and evolving medical management in India, and also indicating future directions in the light of possible resurgence of this disease as pandemic as well as prospective biological threats resulting from acts of bioterrorism. Clinical accounts both in published or prepublication reports from the frontline epicenters were used, incor- porating the evolving flux in guidelines and current controversies, expressed not only in Print media but also video-webinars and conferences constantly in progress. Rather than presenting hard conclusions from the few randomized controlled trials, less formal clinical impressions have been incorporated in the review as it is felt that at this stage of the COVID-19 battle, such data are relevant! Periodic rewriting on this subject is in our Keywords opinion, therefore, eminently desirable (Box format used to allow this). Apart from the ►►COVID-19 respiratory crisis aggravated by cytokine storms, reference is made to the cardiovas- ►►cytokine storm cular, neurological, renal, gastrointestinal, and cutaneous features, these generalized

►►hypoxia manifestations being related to the widespread distribution of angiotensin-converting ►►cardiovascular enzyme-2 receptors in the body as well as to the acute inflammatory hypercoagulop- ►►respiratory athy and disseminated intravascular coagulation typified by hyperacute levels of acute ►►hypercoagulopathy phase reactants as well as the effects of hypoxia-overt or silent!

Introduction 1. Logical time-honored management of the acute respiratory distress syndrome (ARDS) resulting from the acute Any account of the medical management of the corona- SARS-CoV-2 infection and of the cardiac, neurological, virus disease 2019 (COVID-19) illness (henceforth called renal, and endocrine aspects. COVID) caused by the severe acute respiratory syndrome 2. Speculations about the possible benefit from touted inter- coronavirus-2 (SARS-CoV-2) pandemic must be tempered ventions. With regard to the latter, our attitude has been by the disclaimer that this is a rapidly evolving scenario in that at this stage of the pandemic, it is pedantic to wait the context of the spreading pandemic, especially in view of for randomized controlled trials to prove or disprove the the new knowledge from not only the initial China epicenter, efficacy of such interventions. but also from the United States and from Europe. Adding to this are a varying admixture of documented facts, gather- One must also confess that in the absence of limited per- ing knowledge, and speculations, as well the latest version sonal experience in India, the lessons from Italy, the United of ICMR/WHO/CDC/FDA guidelines, which themselves are States, and China as recounted not only in published articles evolving. but also videos, talks, webinars, and the like are considered The outlined advice on medical management of COVID is and incorporated. We would particularly commend the Vu in two categories: Medi series of videos which give practical visual accounts of

DOI https://doi.org/ © 2020. National Academy of Medical Sciences (India). 10.1055/s-0040-1718501 This is an open access article published by Thieme under the terms of the Creative ISSN 0379-038X. Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/). Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India 198 COVID Management: Current and Future Hazra et al.

aspects such as doffing and discarding personal protective Table 1 Post-COVID preparations for the future challenges equipment (PPE), setting up ventilators, management in the Outlining the medical management of COVID cases must be intensive care unit (ICU) during respiratory distress, non-ICU supplemented by some thoughts on India’s preparation for future management of mild cases, and providing radiological inves- emergencies akin to COVID. tigations, etc.1-30 We would also emphasize the role of tele- 1. Development of the biotechnological knowledge base, medicine in managing non COVID disease while our hospitals including National Therapeutic Biomolecule Centers with are coping with both COVID and non-COVID serious patients. associated ICMR supervised low cost limited number clin- Further, as we battle this unprecedented threat, one ical trial centers: such centers were proposed by one of strongly feels that India’s preparation for future challenges the authors (D.K.H.) jointly with Professor V.M. Katoch is a must, some of the salient features of which are listed in (then Director, JALMA, and later Director General, Indian ►Table 1 (But compare ►Supplementary Appendix A, avail- Council of Medical Research, and Secretary, Department able in the online version). Some of the points mentioned in of Health, MoHFW, Govt. of India) to the Department that preparation plan may sound impossibly expensive or of Science and Technology, Govt. of India, as far back Utopian, but may we submit that wise expenditure ahead of as 2005.52 This was modeled on the UK Therapeutic a challenge saves a far greater expenditure/economic/human Antibody Centre at Cambridge/Oxford. Currently the UK cost and loss in the future. Bill Gates in the aftermath of the Centre, is part of the Jenner Institute, which is working on Ebola disaster in 2015 had outlined a plan which might have vaccines including COVID vaccine. been of immeasurable value in dealing with today’s COVID 2. Planning and enforcement of housing norms so that high pandemic! It is heartening to note that the proposed optical population density urban slums like Dharavi are not fiber high speed internet penetration of our remote villages created, and relocation of existing slum dwellers. and the National Digital Health cards as well as the “Make in 3. Manifold strengthening of the medical infrastructure India” strategy are steps in this direction. including creation of a National Health Service coverage of Since many aspects of COVID management are rapidly the entire population. evolving and are in a state of flux, rather than following the 4. Capability to manufacture (and later to export) intensive conventional didactic narrative, Boxes have been created care-oriented medical equipment including ventilators, summarizing current management/considerations. This CPAP, ECMO (extracorporeal membrane oxygenators), would facilitate rapid revision as required with the avail- extracorporeal endotoxin/cytokine removal cartridges, ability of the new evidence-based information 1, 3, 6, and oxygen concentrators, high flow oxygen delivery devices, 12 months in the future. pulse oximeters, dialysis devices as well as enhanced The COVID picture was initially that of a respiratory capability to make rapid diagnostic kits, active pharma- syndrome, analogous to the Flu but over the last few months ceutical ingredients (APIs), and biosimilars. our understanding of the respiratory features has been transformed by the recognition of an insidious silent hypoxia 5. Developing capability for rapid clinical trials to vali- date drugs/strategies and kits, and corresponding (the walking dead) as well as of both H and L forms (►Box A) warranting different management, capable of differentiation pharmacovigilance. by chest X-ray plain films even without computed tomography 6. Creation of 100% adult literacy using electronic media so (CT) chest scans.31 that instructions can be implemented intelligently and The importance of noninvasive differentiation of cardi- expeditiously. ological features from atherosclerotic ischemic syndromes 7. Free and compulsory education for all children to at least has been described in ►Box B. The subject of using class 8 level, Pari passu with the above. renin-angiotensin-aldosterone system (RAAS) inhibitors-ACE 8. Minimal food allowance for every family, including two chil- (angiotensin-converting enzyme) inhibitors or angiotensin dren so that the nutritional health and immune compe- receptor blockers in COVID pandemic era is controversial and tence of the population is built-up. is discussed in ►Box C. The management of diabetes in COVID 9. Salutary punishments for fake drugs. patients who are in danger of a cytokine storm, especially the 10. Quality control, with informational technology support to H variety with waterlogged lungs is described in ►Box D. monitor progress toward objectives 1–9. The changing clinical pictures especially the multisystem involvement including gastrointestinal, neurological, renal, Abbreviations: COVID, coronavirus disease; CPAP, continuous positive airway pressure; ICMR, Indian Council of Medical Research. endocrine, and dermatological presentations are discussed in ►Box E. ►Box F describes the management of the coagulopathy which must be cautious, so as to avoid precipitating bleeding. Convalescent Serum/Plasma Therapy and Serologic ►Box G lists the acute phase reactants that are used to not Testing only arouse suspicion of COVID-19 illness but also assess its Both for diagnosis as well as for selection of convales- severity. cent serum for therapy there is great interest in testing for ►Box H outlines the management of the cytokine storm. antibodies. ►Box I lists factors that adversely affect morbidity and Antigens are detected by examining the nasopharyn- mortality in COVID-19 patients. geal swabs. There are in addition tests for the viral nucleic

Box A Respiratory symptomatology of COVID-19 Box B Ischemic cardiological symptomatology of COVID-19 •• To begin with COVID-19 was regarded as a severe flu-like The ischemic cardiac symptoms are important because Illness. like the pulmonary features they can contribute to dys- •• Consisting of predominantly respiratory symptoms. pnea. Their differentiation from atherosclerotic ischemic cardiac events is important, preferably noninvasively. •• Initially, the COVID infection starts with a common cold or Guidance from the cardiac professional bodies on the flu-like picture: dry cough, sneezes, and nasal/throat con- management of suspected ischemic events in the COVID gestion. This may progress to breathlessness, and finally era, and also with regard to the management of cardiac to a full-fledged ARDS scenario, sometimes necessitating pathology due to COVID-19 is important to understand. ventilator support. The cardiological features of COVID-19 include: •• Later, New York intensivists called attention to: Silent Hypoxia pO2 well below 85 but patient not complaining •• Heart failure/cardiac dilatation/dyskinesia about breathlessness (Walking Dead phenomenon!). In •• BP rise this variety, proning posture/intranasal oxygen/cortico- •• Arrhythmias steroids/C Pap, and treatment of an impending cytokine •• Conduction blocks storm suspected by high IL-6 levels and acute phase reac- •• Troponin-T elevations even to 5,000 tants: troponin-T, ferritin, C-reactive protein, and high •• D-dimer rises even to 30,000 D-dimers, may avoid the need to intubate and ventilate! •• Angina with or without ST,T changes/Q wave •• Radiologically, now H and L varieties described on the basis •• May need fibrinolysis clot busting of CT scans as well as clinical picture: H phenotype with •• Surgical intervention should be avoided to prevent SARS- heavy water-logged lungs, and L phenotype with lighter, CoV-2 transmission less water-logged lungs. H types required ventilation, while Abbreviations: BP, blood pressure; COVID-19, coronavirus disease 2019. L types are harmed by this intervention. •• “It is commonly thought that COVID-19 presents as other individuals willing to do these tests. Simplicity is compara- coronavirus diseases, with ARDS caused by pneumonia-like ble to that of pregnancy testing in the urine! thickening of the lungs. However, recent observations There are many kits under evaluation, some of them using suggest that half of all patients present differently, with CRISP R/Caspase technology to accelerate results. near-normal breathing mechanics, clearer lungs, and ►Box J describes the current status of antibody test- hypoxia caused by poor oxygen transfer to the capillaries. ing as per a recent CDC (Centers for Disease Control and

The ARDS-like H phenotype is characterized by high lung Prevention) guidance note.32 A recent update has also been elastance, high lung weight, and high recruitment (poten- appended on rapid antigen testing. CDC emphasizes that tial to re-expand collapsed lung tissue, e.g., closed alveoli); COVID diagnosis cannot be excluded on the basis of anti- these patients required mechanical ventilation to survive. body tests. The corresponding parameters for the L phenotype are low; ►Box K summarizes prehospital management of sus- applying high-pressure ventilation in these cases can injure pected COVID-19 patient and COVID-19 patient contacts. lungs and precipitate a rapid worsening to ARDS. It is vital to classify patients appropriately. To date, the only way to con- Controversial Agents Used in COVID-19 Therapy firm the phenotypes is through high-resolution computed Hydroxychloroquine tomography. This is inhibitory for rapid triage and impossible Whether HCQ or chloroquine should be used in for hospitals with limited resources. Chest X ray PA achieved” COVID-19 patients with cytokine storm,/all patients/contacts/ this. …(Islam and Fleischer, Princeton, May 3, 2020).31 health care personnel have excited much debate particularly Abbreviations: ARDS, acute respiratory distress syndrome; COVID-19, in view of the alleged cardiac complications! QTc prolongation, coronavirus disease 2019; IL-6, interleukin-6. arrhythmias, and even Torsade-de-pointes and sudden death are alleged to have been induced by these agents. WHO, 202033 acids. Some of the tests are based on caspase technology, suspended this arm of the Solidarity trial. and these are expected to be both rapid and inexpensive, From the point of eye toxicity, HCQ has been thought safer but the problem is to ensure that the particular test can dif- than chloroquine because it does not enter the retinal circula- ferentiate between intact ribonucleic acid (RNA) and RNA tion. It is in use in rheumatoid illness for over 2 decades, and for fragments. The usual tests for RNA are based on polymerase type 2 diabetes mellitus (T2DM) for the past 4 years. Inter alia, chain reactions (PCRs) which require warming as well as it alters the intracellular pH and its benefits in diabetes include involve a turn-around time. Room temperature nucleic reduced hyperglycemia, and anti-inflammatory action. acid detection methods are being devised which not only Logically, a careful analysis of COVID-19 disease expe- are rapid-detection through a color reaction, but capable rience in patients already on such drugs for rheumatoid of being performed by the subject without going to a lab- arthritis/systemic lupus erythematosus/T2DM would be of oratory or hospital. If these tests could be performed on value and has been suggested by Hazra.34 The clinical experi- saliva, they may conceivably be the basis for a self-moni- ence of clinicians at Agra involved in caring for these diseases toring strategy to allow a post-lockout safe resumption of in pre-COVID era has not been adverse! (Agra Diabetes Forum work and the economy. This, of course would depend on video meeting, May 28, 2020: Unpublished Discussion).

Box C RAAS inhibitors and DPP IV inhibitors in the COVID Box D Management of diabetes mellitus in COVID-19 patients scenario •• Old age, diabetes mellitus (DM), heart disease, and even Experts from Australia, etc. were apprehensive that more so, obesity adversely affects complications and mor- hypertensives are not predisposed to infections, so why tality amongst COVID-19 sufferers. It is uncertain whether do so many get COVID infection? Was it due to their use DM increases the attack rate for COVID-19, but it is very of ACE-inhibitor drugs? clear that the morbidity and mortality is much worse Lots of opinions followed! The virus spike protein enters various organs (respira- amongst diabetics. tory, cardiac, endothelial, hepatic, pancreatic, etc.,) cells •• Acute COVID-19 illness requires reevaluation of any through ACE-2 receptors. How RAAS agents modulate medications used for type 2 DM. this entry is still under study and is a subject of debate. •• SGLT 2 inhibitors with risks of dehydration, ketoacidosis, ACE-inhibitors decrease ACE-1 receptors. and fungal infections which are in any case not indicated in Angiotensin II receptor I blocked by ARB—the Sartans. Sartans increase ACE-1 receptors (decrease ACE-2 emergency situations should be stopped. receptors in experimental animals: controversial in •• The glitazones cause fluid retention and therefore may humans). exacerbate the cytokine storm-induced lung pathology and ACE inhibitors increase bradykinin and may induce should therefore be stopped! cough. •• Metformin can cause lactic acidosis in the presence of Sacubitril, like ACE inhibitors also increases bradykinin acute infections! cough and also increases angiotensin II. Cardiological expert bodies advise that: do not withdraw •• Since DPP inhibitors can also affect diverse enzymes other RAAS agents in heart failure/chronic kidney disease/ than DPP-IV only, their use during unknown infections is diabetics with kidney disease in COVID patients. best avoided! But if the indication for RAAS agents is hypertension, the •• Insulin is the glucose-lowering therapy of choice for acute physician can substitute Ca-blockers/diuretics! hyperglycemia. Hyperglycemia is often exacerbated or But avoid starting these in COVID-19 era!: “Primum no precipitated by the steroid therapy used for the cytokine cere”: Hippocrates ACE-2 and DPP-IV enzymes are coronavirus receptors. storm. With insulin preprogrammed pump therapy, only DPP-IV enzyme is a MERS-CoV receptor, but not a SARS- short acting insulins are used. CoV-2 receptor, that is, not a COVID-19 receptor. •• Occasional de novo diabetic ketoacidosis has been observed ACE-2 and DPP-IV enzymes control inflammation and in persons not known to be diabetic! cardiometabolic physiology. •• Potent drugs, including sulfonylureas and long acting DPP-IV inhibitors do not meaningfully modify immune response in humans. insulins which are known to cause hypoglycemia are also COVID-19 hospitalizations are more common among best avoided. people with diabetes and obesity. Abbreviations: DPP-IV, dipeptidyl peptidase-4; SGLT, sodium-dependent Many diabetics, hypertensives, and heart patients are glucose cotransporters. already on ACE inhibitors/angiotensin receptor blockers. ACE inhibitors block ACE-1 and not ACE-2 enzyme. The jury is still out on the use of HCQ. Recent Mediscape There is a suggestion that angiotensin receptor block- 35-39 ers (ARBs) can theoretically reduce coronavirus entry articles just published exemplify the divergent opin- through the ACE-2 receptors but currently, no change ions. Whether HCQ is beneficial for the COVID illness is in existing RAAS medication is advised by cardiological debatable, but with suggested electrocardiogram moni- opinion makers, and some series of studies indicate toring it does not appear to be dangerous! In India both slightly better outcomes in relation to lung damage if ICMR(Indian Council of Medical Research) and AIIMS do these are continued. But conclusive data are still awaited. However, fresh initiation of advocate their use, albeit with EKG monitoring and cau- such agents in the COVID-19 patient is best avoided. Of these, tion, and so do the present authors, based on their safe ARBs are preferred because ACE inhibitors often cause cough, use in rheumatoid arthritis and in diabetes prior to COVID. which can be confusing in COVID-19 situation. Abbreviations: ACE, angiotensin-converting enzyme; BP, blood pressure; Antivirals for COVID Therapy COVID-19, coronavirus disease 2019; DPP-IV, dipeptidyl peptidase-4; Remdesivir MERS-CoV, Middle East Respiratory Syndrome Coronavirus; RAAS, 40 renin-angiotensin-aldosterone system. A preliminary report by Beigel et al from National Institutes of Health based on 1,063 subjects suggested 30% However, the measurement of QTc intervals prior to the reduction in hospitalization time with intravenous (IV) use of these drugs (to identify green/orange or red categories remdesivir (200 mg day 1 loading dose, followed by 100 mg analogous to traffic signals) has been suggested by United IV daily for up to 9 additional days). However, further data States as well as Indian cardiologists and diabetologists! are clearly needed especially with regard to cure rate/viral To avoid relatively hazardous electrocardiography (EKG) burden, etc. recording in COVID in ICU patients, measuring the QTc from the ICU monitor both prior to and subsequent to HCQ admin- Lopinavir/Ritonavir istration has been suggested. A lopinavir/ritonavir combination used earlier in HIV Particular care is needed in patients on azithromycin (human immunodeficiency virus) patients is also being eval- which itself causes QTc prolongation. uated for COVID-19 patients. The results have been rather

Box E Changing clinical pictures and multisystem features Observing the changing clinical picture of the COVID-19 pandemic, from a flu-like lung illness to a multisystem picture, one is reminded of Lorraine Daston’s historical perspective53 To quote her: “Historically, it is natural to cast about for answers at the dawn of a pandemic. At moments of extreme scientific uncertainty, observation, usually treated as the poor relation of experiment and statistics in science, comes into its own. Confronting a new disease, doctors have no choice but to turn to suggestive single cases, striking anomalies, partial patterns. Slowly, as our ideas about what works and what does not help tell us what to test, what to count, the picture clarifies. Until then, we are back in the seventeenth century, the age of ground-zero empiricism, and observing as if our lives depended on it. One patient at a time, we have to work our way into the present!” Why the multisystem involvement?

•• Wide distribution of ACE 2 receptors through which coronavirus enters cells! •• Secondary effects of hypoxia and a generalized acute inflammatory state and the toxic cytokine storm! •• Hypercoagulability, high C-reactive protein, ferritin, D-dimer, N/L ratio: reflecting lymphopenia + neutrophilia, fever. Gastrointestinal symptoms were noted in the Wuhan early reports, but today some subjects have a purely gastrointestinal presentation, long before the chest symptoms. Ageusia: loss of taste (for sweet and salty but sour taste is retained), often with loss of smell (anosmia), diarrhea, nausea/vomiting, abdominal pain, and anorexia can occur. Anosmia was blamed for the direct involvement of the nasal mucosa by SARS-CoV-2. It was also attributed to direct brain invasion of the olfactory cortex from the nasopharynx. Does this occur through the cribriform plate in the skull base-may merit study! Other neurological features that are being noticed include headache, ataxia, and even full-fledged strokes. Surprisingly, these are common in young subjects; abnormal zombie like behavior and confusion have been noted, and encephalopathy has been thought to be present. Renal involvement can occur, and usually carries a bad prognosis, despite dialysis! Acute kidney injury, albuminuria, and raised creatinine can occur. Dermatological features of COVID-19

•• Skin rash •• Chilblains •• Thickened skin on soles analogous to frostbite lesions •• Itching •• Red skin Rash similar to that of frequently reported in Kawasaki syndrome in children: when present, high fatality rate has been observed. Endocrine features:

•• Diabetic ketoacidosis in a previously nondiabetic subject. •• TSH rise despite relatively normal T3 and T4. •• Subacute thyroiditis: single case just reported from Italy: woman aged 18 y who presented with fever, neck pain that radiated to the jaw, and palpitation occurring 15 d after testing positive for SARS-CoV-2 on oropharyngeal swab.29 •• Increased heart rate and a painful and enlarged thyroid on palpation. FT4 and FT3 were high, TSH was undetectable, and inflammatory markers and white blood cell count were elevated. Bilateral and diffuse hypoechoic areas were detected at neck ultrasound. One month earlier, thyroid function and imaging were both normal. “We diagnosed subacute thyroiditis and the patient started pred- nisone,” the authors wrote: “Neck pain and fever recovered within 2 d and the remaining symptoms within 1 week. Thyroid function and inflammatory markers normalized in 40 days.”29 Abbreviations: COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; TSH, thyroid stimulating hormone. disappointing when tried in a difficult group by Cao et al increases drug bioavailability, it is in clinical trials, along from Wuhan.41 The NEJM commented thus: with the immunomodulator interferon β-1b, for the treat- “We have few specific tools to control the growing epidemic ment of Middle East respiratory syndrome (MERS). What and treat those who are sick. We rely on quarantine, isolation, makes lopinavir/ritonavir, particularly attractive is that it and infection-control measures to prevent disease spread and is widely available and manufacturable to scale and that it on supportive care for those who become ill. What we lack is could be prescribed immediately. In fact, there are several a specific antiviral agent to treat the infected and, optimally, case reports and case series where this agent is being used decrease viral shedding and subsequent transmission. against COVID-19. But does it work? One antiviral-drug candidate is a combination of the HIV This is the question that motivated Cao and colleagues to protease inhibitors lopinavir and ritonavir. Lopinavir, which perform an urgent randomized clinical trial of the efficacy acts against the viral 3CL protease, has modest antiviral of lopinavir/ritonavir in patients with COVID-19 in Wuhan, activity against SARS-CoV-2. Together with ritonavir, which China, the epicenter of the outbreak…. The investigators

Box F Managing inflammatory coagulopathy and disseminated Box H Managing the cytokine storm in COVID-19 intravascular coagulation •• When in doubt. Inflammatory hypercoagulopathy prominent in COVID-19: •• Order C-reactive protein/troponin-T/C-reactive protein. •• Dexamethasone along with anticoagulation is the sheet •• Low molecular weight heparin is widely used. anchor (details of dosage are outlined in the final paragraph •• Tissue plasminogen activator (TPA) reopens pulmonary of this review outlining current management as of August vasculature, at least temporarily; hypoxia improves but 20, 2020!). relapses readily. •• Use remdesivir/anti-IL-6 antibodies if available. •• Antithrombin-III (AT-III) advised in Japan: but evidence is •• Inotropes: noradrenaline preferred over dopamine. weak. Also used there in sepsis and disseminated intravas- •• Hydroxychloroquine (HCQ)/azithromycin after checking cular coagulopathy (DIC). QT intervals and watching for changes on the tele-EKG strip •• Hypoxia improves but recurs after TPA withdrawal! without recording formal EKG/Echo (ICMR guidelines as •• Combination of heparin and AT-III therapy may cause issued). bleeding episodes. •• Minimize patient handling. •• It might be time for reconsidering the interaction and mod- •• Convalescent serum and injectable hyaluronidase /niacin ulation of different connected systems, e.g., coagulation, have been reported beneficial in anecdotal cases. fibrinolysis, Kallikrein-Kinin, complement and immunity (cytokine storm). An algorithm for optimizing therapy has Abbreviations: EKG, electrocardiography; ICMR, Indian Council of Medical Research. been proposed by Seitz and Schram recently in 2020, who have described rational strategies for attenuating DIC in 23 COVID-19. Box I Factors increasing morbidity in COVID-19 Abbreviation: COVID-19, coronavirus disease 2019. •• Diabetes mellitus •• Hypertension •• Cancer Box G Acute phase reactants used for diagnosis of COVID-19 •• Preexisting heart disease Lymphopenia even below 800/µL +Neutrophilia: elevated N/L ratios •• High BMI (even more so than merely diabetes!) •• Black, in contrast to Caucasian genetic background •• Elevated Troponin-T •• Male sex as compared with female sex

•• Elevated D-dimer >1,000 ng/mL •• Group A blood type •• Elevated CPK-MB greater than two times normal Abbreviations: BMI, body mass index; COVID-19, coronavirus disease 2019. •• Elevated C-reactive protein (CRP) •• Raised ferritin (>500 µg) •• Elevated LDH, ALT (SGPT), and AST (SGOT) •• Elevated IL-6 16 days. But the results for certain secondary end points •• Elevated Von Willebrand factor (VWF), consistent with are intriguing. A slightly lower number of deaths was seen endothelial injury in the lopinavir/ritonavir group, although this observation is •• Increased factor VIII activity difficult to interpret….both groups were heterogeneous and received various additional treatments, including other phar- Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK-MB, creatine kinase myocardial band; IL-6, interleukin-6; LDH, macologic interventions such as interferon (11%) and gluco- lactate dehydrogenase; SGOT, serum glutamic oxaloacetic transaminase; corticoids (34%)…. SGPT, serum glutamic pyruvic transaminase. Tellingly, though, there was no discernible effect on viral shedding. Since the drug is supposed to act as a direct recruited patients who had an oxygen saturation of 94% or inhibitor of viral replication, the inability to suppress the less while they were breathing ambient air or a ratio of the viral load and the persistent detection of viral nucleic acid partial pressure of oxygen to the fraction of inspired oxygen strongly suggest that it did not have the activity desired…. of less than 300 mm Hg and who were receiving a range of Two major factors may be in play. First, the authors chose a ventilatory support modes, from nothing to mechanical ven- particularly challenging population. The patients recruited tilation or extracorporeal membrane oxygenation (ECMO). for the study were late in infection and already had con- …. All the patients received standard care, and half were siderable tissue damage (as evidenced by compromised randomly assigned to receive lopinavir/ritonavir for 14 days. lung function and 25% mortality in the control group). Even The primary end point was the time to clinical improvement, highly active antibacterial agents have limited efficacy in defined as the time from randomization to either discharge advanced bacterial pneumonia. Second, lopinavir simply is from the hospital or improvement on a multifactorial set of not particularly potent against SARS-CoV-2. The concentra- prespecified criteria, whichever came first. The trial aimed to tion necessary to inhibit viral replication is relatively high enroll 160 patients…... as compared with the serum levels found in patients treated Unfortunately, the trial results were disappointing. No with lopinavir/ritonavir….In addition, 42% of the patients benefit was observed in the primary end point of time to were viral load-positive at day 28, but the quantitative data clinical improvement: both groups required a median of at that point show that the levels were low, probably near

Box J Antibody testing •• “Point-of-care and laboratory-based serologic assays for SARS-CoV-2 now have Emergency Use Authorization (EUA) by the U.S. Food and Drug Administration (FDA), and their performance has been independently reviewed. •• Currently, there is no identified advantage of assays whether they test for IgG, IgM, and IgG, or total antibody. •• It is important to minimize false positive test results by choosing an assay with high specificity and by testing populations and individuals with an elevated likelihood of previous exposure to SARS-CoV-2. Alternatively, an orthogonal testing algorithm (i.e., employing two independent tests in sequence when the first test yields a positive result) can be used when the expected positive predictive value of a single test is low. •• Antibodies most commonly become detectable 1–3 wk after symptom onset, at which time evidence suggests that infectious- ness likely is greatly decreased and that some degree of immunity from future infection has developed. However, additional data are needed before modifying public health recommendations based on serologic test results, including decisions on discontinu- ing physical distancing and using personal protective equipment (PPE).” Antigenic targets The two major antigenic targets of SARS-CoV-2 virus against which antibodies are detected are spike glycoprotein (S) and nucleocap- sid phosphoprotein (N). While S protein is essential for virus entry and is present on the viral surface, N protein is the most abundantly expressed immunodominant protein that interacts with RNA. Multiple forms of S protein—full-length (S1+S2) or partial (S1 domain or receptor binding domain [RBD])—are used as antigens. The protein target determines cross-reactivity and specificity because N is more conserved across coronaviruses than S, and within S, RBD is more conserved than S1 or full-length S. Types of antibody testing Different types of antibody testing assays can be used to determine different aspects of immune response and functionality of antibodies. The tests can be broadly classified to detect either binding or neutralizing antibodies.

•• Binding antibody detection: These tests use purified proteins of SARS-CoV-2, not live virus, and can be performed in lower biosafety level laboratories (e.g., BSL-2). With specific reagents, individual antibody types, like IgG, IgM, and IgA, can be determined. In general, IgM is one of the first types of antibodies produced after infection and is most useful for determining recent infection, while IgG generally develops after IgM and may remain detectable for months or years. IgA is important for mucosal immunity and can be detected in mucous secretions like saliva in addition to blood, though its significance in this disease is still to be determined. Depending on the complexity of assays, these tests can be performed rapidly (less than 30 min) in a field setting or in a few hours in a laboratory.

Tests that detect binding antibodies fall into two broad categories:

1. Point-of-care (POC) tests generally are lateral flow devices that detect IgG or IgG and IgM, or total antibody in serum, plasma, whole blood, and/or saliva. An advantage of some point-of-care tests using whole blood is that they can be performed on blood samples obtained by fingerstick rather than venipuncture. 2. Laboratory tests use ELISA (enzyme-linked immunosorbent assay) or CIA (chemiluminescent immunoassay) methods for antibody detection, which for some assays may require trained laboratory technicians and specialized instruments. Based on the reagents, IgG, IgM, and IgA can be detected separately or combined as total antibody titer.

•• Neutralizing antibody detection: FDA has not yet authorized the use of neutralization tests (NT) for SARS-CoV-2. NT determine the functional ability of antibodies to prevent infection of virus in vitro. The test involves incubating serum or plasma with live virus followed by infection and incubation of cells. Testing will require either BSL-3 or BSL-2 laboratories, depending on what form of the SARS-CoV-2 virus is used. Two types of neutralization tests are conducted.

1. Virus neutralization tests (VNT), such as the plaque-reduction neutralization test (PRNT) and microneutralization, use a SARS- CoV-2 virus from a clinical isolate or recombinant SARS-CoV-2 expressing reporter proteins. This testing requires BSL-3 laboratories and may take up to 5 d to complete. 2. Pseudovirus neutralization tests (pVNT) use recombinant pseudoviruses (like vesicular stomatitis virus, VSV) that incorporate the S protein of SARS-CoV-2. This testing can be performed in BSL-2 laboratories depending on the VSV strain used. Abbreviations: IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin C; RNA, ribonucleic acid; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2. the threshold of detection. Since the test detects nucleic acid, which was recently approved in Russia. This drug and DAS positive results do not necessarily indicate the production of 181 are being evaluated. infectious virus. These data suggest that assessing transmis- Oseltamivir (Tamiflu) has not been reported to be effec- sibility after recovery from severe disease will be a priority to tive, though it was very useful in earlier swine flu epidemics! help control transmission…” EIDD 2801: This is another promising antiviral from the Emory University, resembling remdesivir, which Favipiravir, Ostelamivir/EIDD 2801 has just received FDA (Food and Drug Administration) Other antivirals, such as favipiravir, are also being studied… approval for human clinical trials (EMORY news center This is an Indian generic version of the Japanese drug Avigan April 7, 2020).42 Unlike remdesivir, which has to be given

Box K Prehospital management of suspected COVID-19 patient Agents That Are Promising and COVID-19 patient contacts Colostrum of bovine origin, various folk medicines both •• Do not panic from Chinese and Ayurvedic medicine, (including Giloy and Tulsi—Tinospora cordifolia and Ocimum sanctum) as well as •• Watch pO2 with pulse oximeter •• Test for acute phase reactants: ferritin, troponin-T, Homeopathy are undergoing trials as preventive agents. C-reactive protein, neutrophil/lymphocyte ratio, Ivermectin (12 mg weekly), high doses of vitamin C, zinc, measure body temperature daily preferably with an selenium, inositol, and niacin all have been suggested as pre- infrared thermometer ventives or as therapy. Unlike HCQ there are no toxic effects •• Quarantine/self-isolate /including PPE-masks/plastic shields/ reported. After robust in vitro efficacy reports from Monash 44 45 gloves, and gowns. University, Australia, Alam from Bangladesh claimed that •• Stay in touch with your doctor (telemedicine). 60 patients treated with a combination of ivermectin and •• Play solitaire doxycycline recovered within 4 days. The data were being •• Pray prepared for publication. •• Read Unlike azithromycin, doxycycline has not been reported to •• Listen to music/see TV cause QTc prolongation. •• Repeat COVID-19 testing at 7/14/28 days We suggest that it would appear logical to try out low cost combinations of doxycycline, ivermectin, HCQ, EIDD 2801, Abbreviations: COVID-19, coronavirus disease 2019; PPE, personal protective equipment. and azithromycin—all being oral drugs, not needing costly, hazardous hospitalization. intravenously, EIDD-2801 can be given orally as a pill. It is an Results of Indian studies with herbal and homeopathic orally bioavailable prodrug of the synthetic ribonucleoside drugs (Gupta, Pradip: Personal Communication) are awaited. derivative of β-D-N4 hydroxy cytidine (NHC/EIDD-1931) It is hoped that these are conducted with scientific rigor. as 5-isopopylester (EIDD2801). Its parent compound NHC/ EIDD-1931 has been shown to have broad spectrum antivi- Convalescent Serum ral activity against SARS-CoV-2, MERS-CoV, and SARS-CoV. If •• This has been suggested as a safe intervention in sick 46 EIDD-2801 is shown to be safe and effective, people could patients. Casdevali et al give an excellent overview of take it at home rather than in a hospital. That would allow discussed risks and benefits. Measurement of antibody EIDD-2801 to be taken earlier in the course of the disease, levels and nature of antibody present would be useful, killing off the virus before it wreaks havoc on the body. but empirically this is being used with benefit at various EIDD-2801’s other intriguing feature is that it appears to centers in India, and ICMR in India and the FDA in United have a high barrier to resistance. Drugs can force viruses to States have approved this as compassionate use. No clini- quickly develop mutants that are not affected by the drug, cal trials are feasible in such extremely sick patients! which then makes the drug obsolete. But EIDD-2801 has not prompted that sort of resistance in laboratory tests despite IL-6 Inhibition efforts to coerce such mutants to arise. With hints that •• Measurement of interleukin-6 (IL-6) as an acute phase EIDD-2801 and its active metabolite, the triphosphate of index of a cytokine storm often shows very high levels. EIDD-1931, might be able to fight other RNA viruses, Painter tumor necrosis factor-α and IL 1 are not as high! and his collaborators began testing it against Ebola, chikun- Tocilizumab is a monoclonal antibody that blocks both 47 gunya, and influenza. It knocked them all out. For example, membrane-bound and circulating IL-6 receptor. It is just three doses of EIDD-2801 could save ferrets (animals being tried at some centers to treat the cytokine storm. commonly used to study human respiratory viruses) infected Sarilumab is another anti-IL-6 monoclonal being with influenza from the 2009 H1N1 pandemic. evaluated.

Interferon-ALPHA-2b 38 Recently interferon-α-2b is attracting attention in viral Other Agents Being Evaluated treatment.43 Vitamin D to enhance macrophage function, IL-1 inhibitors such as anakinra, nitric oxide, JAK inhibitors, baricitinib, Corticosteroids pacritinib, ruxolitinib NMDA (N-methyl-D-aspartate), Logically corticosteroids were suggested to reduce the mesenchymal cells are other agents undergoing phase I/II inflammation of the cytokine storm. After the Recovery or III trials but they are still far from being in routine use! trials from Oxford showed reduction in mortality they Dipyridamole, monoclonal antibodies, famotidine, thymosin are now in widespread use! The penultimate paragraph alpha, acalabrutinib, BCG (Bacillus Calmette–Guérin) vacci- on COVID management in August 2020 describes current nation, p38MAPK inhibitors, and colchicine have also been usage protocols. referred to in recent reviews.39,48

Postscript: Outline of Present-Day COVID Management as of With regard to anticoagulation, enoxaparin (Inj Clexane) August 20, 2020 used is 0.5 mg s/c bd if D-dimer is normal, and 1 mg s/c bd if This is partly based on a recent review by David Cenmino D-dimer is elevated. After 5 days, one can switch to oral antico- in Medscape updated August 20, 2020! COVID-19 treatment agulant Tab rivaroxaban 10 mg od for 4 weeks. It is debated when and management49 as well as a Karnataka Medical Association to start anticoagulants. Better to start it early if CT changes are Guidance note dated August 14, 2020.50 seen, as the changes in CT are actually microvascular thrombi. Once COVID is diagnosed or strongly suspected, obtain a If oxygen is needed, anticoagulation must be continued for 6 baseline pulse oximetric pO2, Hb, total leukocyte count, dif- weeks. Early steroids and anticoagulant will prevent long-term ferential leukocyte count (to estimate neutrophil/lymphocyte complications, even if they do not show benefit in the acute ratio), erythrocyte sedimentation rate (ESR), C-reactive pro- phase! Both are mandatory if there is hypoxia. tein, D-dimer, IL6 (if available), lactate dehydrogenase (LDH), It has been opined that HCQ should not be combined with ferritin, Trop T, baseline liver, and kidney function tests espe- remdesivir. cially SGPT or serum glutamic pyruvic transaminase (ALT or It is mandatory to monitor CRP, D-Dimer every alternate day alanine aminotransferase), S creatinine, ECG, baseline chest till patient is in hospital: IL6 on day 5 and day 8. Any rise in IL6 is X-ray, and CT chest. a marker for an impending cytokine storm and it might be use- Even CT changes may be late but CRP and LDH are the ful to start tocilizumab if symptoms worsen. IL6 can return to first to rise. Clinically the three dangerous symptoms are normal with steroids and anticoagulant. If tocilizumab is given fever, myalgia, and exhaustion which indicate high inflam- procalcitonin should be monitored for secondary infection and mation in the body. Feverish feeling without actual fever the risk of infection is present for the next 2 weeks. Once tocili- may occur! zumab is given patients may not manifest fever or raise counts Nasopharyngeal smear may be negative, even if sup- despite existence of infection. Antibiotics may be used depend- plemented by RT-PCR and also antibody tests. Best time ing on the community usage. Doxycycline is safe. Azithromycin for RT-PCR after symptom onset is fifth to eighth day. can cause QTc prolongation and should not be used in combina- False negatives are least during this period. RT-PCR may be tion with hydroxychloroquine. negative in late stages of infection. One must therefore base With regard to prognosis, the dangerous period is 8 to one’s diagnosis on clinical, epidemiological, and radiological 12 days, when mortality is the greatest. Rarely late cytokine clues. The r replication score in RT-PCR test indicates how storms after 12 days are seen. infective a subject is for others. Any score above 25 is gen- But if treatment is started early with steroids and anti- erally noninfectious especially if it is beyond 10 days and coagulants complications are unlikely. Again, to reiterate there have been no symptoms for 3 consecutive days. Viral it is the inflammation which kills, not the virus. If one hits replication generally stops by nineth day which implies that inflammation and coagulopathy hard and early, one should, if one expects any benefit of antiviral therapy it should be Deo Gratia, avoid complications, and the body will eliminate given within 9 days. There is doubt regarding the efficacy of the virus. remdesivir, if given late. Proning makes a marked difference in managing hypoxia. It is the inflammation which damages not the virus. COVID, Radiologically, CT chest need not be repeated after the systemic lupus erythematosus, antiphospholipd syndrome, base line because excessive radiation may exacerbate lung type 1 diabetes mellitus macrophage activation syndrome, injury: repeat X-ray chest after 3 days suffices, and artificial and hemophagocytic lymphohistiocytosis are all similar... intelligence is being looked at for interpreting these X-rays. Host immune system reacts against its own tissues... ““ Remember radiological changes may take long to clear, as Frustrated phagocytosis ““ occurs when the antigen cannot these shadows are lung clots not inflammation! be eliminated leading to hyperactivation of macrophages and Improvement in oxygen levels is the marker for clinical lymphocytes leading to destruction of tissues. improvement. and the most reliable indicator of patient status. Steroids and anticoagulation are the corner stones of treat- If antibody levels are good, the subject’s convalescent serum ment. At present steroids are recommended for people who may help a critical ill patient of the same blood group recover! become hypoxic. But one should start steroids early irrespective Antibody Status and Return to Work of hypoxia if CRP and other inflammatory markers are elevated. About 10 to 15% of the patients do not develop antibodies Oral prednisolone 20 mg or dexamethasone 4 mg/d for post COVID. Perhaps some subjects do not develop antibod- 5 to 7 days is used if the symptoms are mild. Steroids not ies, or develop some T-cell immunity, or have dominant IgA only make the patient feel better but more importantly pre- antibody response in respiratory mucosa instead of a t sys- vent long-term lung fibrosis, and its specter of lung trans- temic IgG response plantation! In severe cases, injection of methylprednisolone Relapse can occur: therefore, continue to follow anti COVID 40-mg intravenous bd or tid is based on weight and severity precautions! Follow strict safety protocols post COVID too. of hypoxia. Steroids do cause hyperglycemia and may precipitate diabetes but this is easily managed with soluble insulin. Summary One changes to oral dexa once the course of antiviral is fin- ished. Steroids may be needed for 2 to 3 weeks if hypoxia is The battle with the coronavirus has just been joined. Let us present. Since steroids are diabetogenic, sugars must be mon- pray that men of medicine and science continue to improve itored regularly as long as patients are on steroids. management. The struggle to obtain a safe vaccine is good

but let us remember that defeating the earlier optimism in 9 Jaffe A. What Does Elevated Troponin Mean in COVID-19? Vu some diseases such as HIV and Dengue, we still do not have MediVideo, May 2020; 2020 a vaccine. For rabies, smallpox, and tuberculosis (TB) on the 10 Jain T, et al. Potential Effects of COVID-19 on the Cardiovascular System: How to Treat ST-Elevation on EKG? Why Are STEMIs other hand vaccines dating back to Pasteur and Jennings Going Down During the Pandemic? New York, NY: Mount Sinai have been spectacularly successful. BCG inoculation mod- Vu MediVideo, May 2020; 2020 ified the TB onslaught and reduced the death rates from 11 Mahmood K, et al. ARDS and COVID-19 in an LVAD Patient: tubercular meningitis, even though they did not eliminate Should We Look at Percent Change in LDH, Ferritin and CRP TB. Also, the Holy Grail vaccines should not precipitate dan- Values in A Cytokine Storm to Assess Severity? What Cardiac Manifestations Do We Need to Keep an Eye on? New York, NY: gerous or lethal immune reactions! Mount Sinai Vu MediVideo, May 2020; 2020 Men of economics and industry and those leading the 12 Mascarenhas J. Can Pacritinib Be Used to Treat Cytokine Storm Government, should try to prepare for and prevent future in Patients With COVID-19? What Was the Primary End Point pandemics, perhaps looking to what we have sketched out of the Trial & Which Patients Are Eligible for the Treatment? in the ►Table 1. Recent CDC guidelines51 make instructive New York, NY: Mount Sinai Vu MediVideo, May 2020; 2020 reading, while the nation gears up for the post lockdown 13 Moll S. COVID-19 Coagulopathy: What is the PE and DVT Risk? How Should We Optimize the Anticoagulation Therapy era and the problems related to our hardworking migrant Algorithm?(Describes Current UNC Algorithm) Vu MediVideo, labor. May 2020; 2020 Social distancing and hand sanitation are interim mea- 14 Narula J, Sharma S. STEMI Patients with COVID-19: What sures, while cure/vaccine options are developed. All human Cardiovascular Manifestation Are Expected in Patients? What beings including the Readers and Health Care Workers Is the Management Protocol to Treat Them? New York, NY: are requested to not only protect themselves but also set Mount Sinai Vu MediVideo, May 2020; 2020 15 bok15. Olin J. COVID-19: What Types of Thrombosis Are examples! Commonly Seen? Are Anticoagulants Effective & How to Use them? New York, NY: Mount Sinai Vu MediVideo, May 2020; Conflict of Interest 2020 /bok None declared. 16 Olin J, et al. COVID-19 and Stroke: Is Large-Vessel Stroke a Presenting Feature of COVID-19: in the Young? Should We Monitor These Patients with Blood Work, Antiplatelet, References or Antithrombotic Therapy? Is There a High Bleeding Complication Rate? New York, NY: Mount Sinai Vu MediVideo, 1 Chidinma Chima Melton. Management of Critically Ill May 2020; 2020

COVID-19 Patients. What Are the Protocols at UCLA Health? 17 Olin J, et al. What Biomarkers Are Recommend for Looking for Vu Medi April 2020, 28–36; 2020 Pulmonary Embolism in COVID-19 Infected Patients? Are They 2 Cordon-Cardo C. COVID-19: What Is the Benefit of Good for Diagnostic Purposes? New York, NY: Mount Sinai Vu Antithrombotic Therapies & What Is the Prothrombotic MediVideo, May 2020; 2020 Nature of the Disease? Does Hypoxia Induce Organ Damage 18 Olin J, et al. COVID-19: Are You Requiring PCR Testing for or Is It a Multi-organ Disease? New York, NY: Mount Sinai Vu All In-person Encounters and What Is the Turnaround Time? MediVideo; 2020; 2020 How Do You Protect Staff? New York, NY: Mount Sinai Vu 3 Cordon-Cardo C, Garcia-Sastre A. COVID-19: What Determines MediVideo, May 2020; 2020 a Person’s Immune Response? When Is the Right Time to Do 19 Olin J, et al. Venous Thromboembolism & COVID-19: Has Antibody Testing & How Do You Determine What Degree of There Been an Increased Incidence at Mount Sinai Health Antibody Response Is Protective? New York, NY: Mount Sinai System? What About Performing Mechanical Thrombectomies Vu Medi Video; 2020 in Critically Ill Patients? New York, NY: Mount Sinai Vu 4 Cordon-Cardo C, Patel G. COVID-19 Medication Responses MediVideo, May 06, 2020:53; 2020 from Mount Sinai: What Should We Know about 20 Olin J, et al. What Is the Role of Endothelial Dysfunction Hydroxychloroquine, Steroids, Remdesivir and Plasma? In in the Vascular Complications Associated with COVID-19 What Situations Is Plasma Treatment Effective? Do We Know Patients? Why Do We See So Much Thrombosis in These What Doses to Give? New York, NY: Mount Sinai Vu Medi Patients? New York, NY: Mount Sinai Vu MediVideo, May Video; 2020 2020; 2020 5 Cordon-Cardo C, et al. COVID-19: Will There Be a Second Wave 21 Osterholm M, hVuMedi, May 2020: Possible Scenarios for the of Infection and Will the Virus Virulence Change in Time? New Course of the COVID-19 Pandemic: Are We Prepared for at Least York, NY: Mount Sinai Vu MediVideo, May 2020; 2020 Another 18 to 24 Months of Significant COVID-19 Activity? 6 Cordon-Cardo C, et al. COVID-19 Testing Challenges: What VuMediVideo, May 2020; 2020 Is the Importance of Testing for Diagnosis and Stratifying 22 Reddy V, Bokhari M. Electrophysiological Analysis of Two Cases Patients by Viral Load? What Is the Possibility of a False of COVID-19 Patients: How do Plaquenil, Chloroquine and Positive or False Negative Test? New York, NY: Mount Sinai Vu Azithromycin Effect the Cardiovascular System? What Causes MediVideo, May 2020; 2020 Troponin Elevation in COVID-19 Patients with Myocardial Injury? 7 Garcia Sastre A, Narula J. COVID-19: What Are Most of the New York, NY: Mount Sinai Vu MediVideo, May 2020; 2020 Vaccines Based On& What is the Main Focus in Neutralizing 23 Seitz and Schram. Rationale for Developing Strategies for Antibodies Against the Receptor Binding Protein? New York, Attenuating DIC in COVID-19. Vu MediVideo, May 2020; NY: Mount Sinai Vu MediVideo, May 2020; 2020 2020 8 Griffin D. COVID-19 Patients: Which Drug to Prescribe, 24 Serrao GL2020: Refractory ARDS & COVID-19: Why Should VV When, and to Whom? What Are Some Cardiac, Cognitive & ECMO Work and When Should It Be Used? Which Patients Are Neurological Clinical Manifestations, and Who Should Receive Good Candidates for ECMO? New York, NY: Mount Sinai Vu Anticoagulants. Vu MediVideo, April 2020; 2020 MediVideo, May 2020; 2020

25 Serrao G. ECMO for COVID-19: Should It Be Used to Treat ARDS 39 American College of Physicians. COVID-19: An ACP Physician’s & How to Deal with Recirculation Problems? Why Is It Hard Guide + Resources. Available at: https://www.acponline.org/ to Use VV ECMO in Patients with High Cardiac Output States? clinical-information/clinical-resources-products/coronavirus- Has the Use of Remdesivir in Combination with ECMO Shown disease-2019-covid-19-information-for-internists to Be Successful? New York, NY: Mount Sinai Vu MediVideo, 40 Beigel JH, Tomashek KM, Dodd LE, et al; ACTT-1 Study Group May 2020; 2020 Members. Remdesivir for the treatment of COVID-19—prelim- 26 Serrao G. Shock in COVID-19 Era: How to Treat Different Types inary report. N Engl J Med 2020;383(10):994 of Circulatory Shock? Does Placing Univentricular Support 41 Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritona- Risk Precipitate Frank Failure of the Other Ventricle? Why vir in adults hospitalized with severe COVID-19. N Engl J is IABP the Preferred Approach over ECMO? New York, NY: Med 2020;382(19):1787–1799 Mount Sinai Vu MediVideo, May 2020; 2020 42 Emory News Center. FDA: Human Trials can Begin for 27 Warner JP. (Codman Shoulder Society):Post-Pandemic Emory COVID-19 Antiviral. Available at: News emory.edu/ Orthopedic Care: Challenges &Opportunities. VuMediVideo, stories/2020/04/COVID EIDD 2801-FDA/index/html; 2020 May 2020; 2020 43 Zhou Q, Chen V, Shannon CP, et al. Interferon-α2b treatment 28 Herold T, Jurinovic V, Arnreich C, et al. Elevated levels of for COVID-19. Front Immunol 2020;11:1061 IL-6 and CRP predict the need for mechanical ventilation in 44 Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The COVID-19. J Allergy Clin Immunol 2020;146(1):128–136.e4 FDA-approved drug ivermectin inhibits the replication of 29 Brancatella A, Ricci D, Viola N, Sgrò D, Santini F, SARS-CoV-2 in vitro. Antiviral Res 2020;178:104787 Latrofa F. Subacute thyroiditis after Sars-COV-2 infection. J Clin 45 Alam MT. Bangladesh Medical Team Says Ivermectin with Endocrinol Metab 2020;105(7):2367–2370 Antibiotic Doxycycline Works to Treat COVID 19 Patients. New 30 Hick JL, Biddinger PD. Novel coronavirus and old lessons— Delhi: Press Trust of India release May 19, 2020; 2020 preparing the health system for the pandemic. N Engl J 46 Casadevali A, Joyner MJ, Pirofski LA. A randomized trial of Med 2020;382(20):e55 convalescent plasma for COVID-19-potentially hopeful signs. 31 Islam MT, Fleischer JW. Distinguishing L and H phenotypes JAMA 2020;324(5):455–457 of COVID-19 using a single x-ray image (Prepublication). 47 Sebba A. Tocilizumab: the first interleukin-6-receptor inhibi- Available at: https://doi.org/10.1101/2020.04.27.20081984. tor. Am J Health Syst Pharm 2008;65(15):1413–1418 Accessed May 3, 2020 48 American College of Physicians. Coronavirus Disease 2019 32 Interim Guidance for Rapid Antigen Testing for SARS-CoV-2. (COVID-19): Information for Internists. Available at: https:// Available at: https://www.cdc.gov/coronavirus/2019-ncov/ www.acponline.org/clinical-information/clinical-resourc- lab/resources/antibody-tests-guidelines.html and July 27 es-products/coronavirus-disease-2019-COVID-19-informa- 2020 update https://www.cdc.gov/coronavirus/2019-ncov/ tion-for-internists hcp/testing-overview.html and https://www.cdc.gov/corona- 49 Cenmino D. Corona Virus Disease 2019 (COVID-19) Treatment virus/2019-ncov/lab/resources/antigen-tests-guidelines.html. and management: Updated 20 August 2020. Medscape; 2020

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THIEME 208 UniversalReview Article Health Coverage in India Nanjunda

Universal Health Coverage in India: Where Rubber Hits the Road?

Devajana Chinnappa Nanjunda1

1Centre for the Study of Social Exclusion and Inclusive Policy, Address for correspondence D.C. Nanjunda, D.Litt., Centre for Humanities Block, University Of Mysore, Mysore, Karnataka, India the Study of Social Exclusion and Inclusive Policy, Humanities Block, University of Mysore, Mysore 570006, Karnataka, India (e-mail: [email protected]).

Ann Natl Acad Med Sci (India):2020;56:208–213

Abstract Poverty and healthcare issues are the most debatable topics today. Developing countries like India have as much as 45% of its population trapped in poverty because of various urgent healthcare needs. Universal health coverage (UHC) is a unique insurance system to provide financial protection to the marginalized groups of the country. It facilitates appropriate and immediate health needs, including required diagnostic, therapeutic and operational costs. However, UHC, a unique plan which focuses on the disadvantaged sections of the society, has some serious lacunae when it comes to its implementation in real life. This includes finances and human resources. Experts are reallocating adequate budgetary expenditure on healthcare issues, and in the mean- time, a shortage of skilled health manpower is hunting down the UHC scheme in India. In recent times, different state governments are increasing budget allocation for the health sector. UHC is targeting low-income and poor families, forgetting the afford- Keywords able and timely healthcare by way of improving services offered at the primary health

►►universal health centers and rapid expansion of the skilled health manpower across the country. UHC coverage needs to focus on health paradigm systems, including improved healthcare-seeking ►►health behavior, nutrition, sanitation, potable water, reducing maternal and infant mortality, ►►Ayushman Bharat and dissemination of information of current technology to provide quality health ser- ►►poverty vices to the underserved and marginalized population of the country. These changes ►►cost would symbolize a real way forward toward the immediate fulfillment of UHC goals for ►►quality India.

Introduction to appropriately manage public and private actions, and investments in health” 1 In 1998, the World Health Assembly made new commit- The Government of India and State Governments have the ments to ‘Health for All’ for the 21st century. The commit- general obligation to extend free universal health coverage ment included, in part, “we commit ourselves to strengthen, (UHC) services, and ensure that the marginalized sections of adapting and reforming as appropriate our health systems the society should be in a position to obtain quality health- including essential public health functions and services to care services, directly or indirectly, offered by any healthcare ensure universal access to health services that are based on service provider at any given point in time. The strange thing scientific evidence of good quality and within affordable lim- is India is exporting software to the Western countries, but it its, and that are sustainable for the future. We will continue to trails in health outcomes when compared with Bangladesh develop health systems to respond to the current and antic- and Sri Lanka! The 11th 5-year plan has set goals for reduc- ipated health conditions, socio-economic circumstances and ing maternal and infant mortality, increasing child sex ratio, the needs of people, communities and countries concerned and reducing malnutrition among children and women in

DOI https://doi.org/ © 2020. National Academy of Medical Sciences (India). 10.1055/s-0040-1713708 This is an open access article published by Thieme under the terms of the Creative ISSN 0379-038X. Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/). Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India Universal Health Coverage in India Nanjunda 209 the country. The same five year includes states health for all for the health sector for the purpose of health inclusion. The marginalized groups at a reasonable cost. On this issue, the National Health Policy of 2017 governments is intended to Government of India has set minimum standards and req- spend at least 70% of the total healthcare budget for only pri- uisite control mechanisms or systems, focusing on paneled mary healthcare centers (PHCs) (►Figs. 1–3). health providers.2 This new UHC health scheme is a much awaited health Today, health exclusion has become one of the major con- program because it reduces the catastrophic health expen- cerns, because of which inclusive development is not possible diture on the part of the poor patient, and it also indirectly in a country like India. Since time immemorial, poverty and helps the quality services on the part of the government health problems are intertwined. Poverty plays a very crucial hospitals. Ayushman Bharat has two major segments–1. role in the onset of various simple and complicated health National Health Protection Scheme and 2. creation of well- problems. The then planning commission had estimated that ness centers in place of subcenters. The national health pro- 39 million people are afflicted with various health problems tection scheme has two major agendas–1. pressing the need just because of poverty. Around 47% in rural area and 31% in for good network among health and wellness infrastructure urban areas people are taking loans and selling assets just to across the country to deliver quality healthcare services and attend to their health needs. Moreover, the same report says 20% in urban areas go untreated due to financial constraints and 30% in the case of rural India.3 Providing timely finances for the health and healthcare of the needy is a significant issue; it is the building block of any health system and critical to a well-performing healthcare system. As we know, many poor Indian states are struggling to get sufficient funding for health and healthcare needs. Moreover, many developed Indian states have still not scien- tifically prearranged their different health services to make sure equitable, affordable and easily accessible and universal healthcare for all walks of life and geographies.4 Also, the health sector in India suffers from inadequate funding, shortage of skilled health professionals, failure of the health programs, issues in healthcare management, Fig. 1 Out-of-pocket health expenditure as proportion of total health expenditure. weak institutional regulatory system, and neglecting traditional systems of medicines. Today, the healthcare system has become highly commercialized, and only the rich people can access quality healthcare. It is also quite evident to write that the healthcare system in the country suffers from poor health infrastructure, especially in rural and tribal settings. Even today in rural areas, people are not getting quality health services because of poor management and lack of infrastructure in rural-based government hospitals as per the recent Niti Aayog report. There are interstate disparities and differences between rural and urban health indicators in India. There is a target to provide safety, health and environment to its citizens through universal quality healthcare services, and regulatory mechanisms in the part of the private healthcare sector, by the year 2025; also, to increase the GDP Fig. 2 Government health expenditure as proportion of GDP. allocation for the health sector gradually.5 Aayushman Bharat is an iconic UHC Program of India to fulfil its promise in the National Health Policy of 2017. Ayushman Bharat Yojana or National Health Protection Scheme is a program to provide quality healthcare services to more than half of the total underserved Indian population. The socioeconomic caste census database shall be utilized to recognize needy beneficiaries for this scheme in the country. As we know in India, expenditure on healthcare for the year 2013–2014 was about around 4.02% of the total GDP, and the government share was just 1.15% against 5.99% of the global average. The government is committed to hik- ing money for UHC in budgetary allocations of 2.5 percent of GDP by 2025.6 Currently, India is using 0.1% of total GDP Fig. 3 Population coverage under various health schemes in India.

2. the most important point is to deliver integrated health- and simulated across all government hospitals. Cross-cutting care service through insurance coverage, covering, at least, technical areas with clear linkages with quality UHC is a 50% of India's population who are under below the poverty necessity in case of public health functions and health-related line or deprived sections.7 issues. There is a big issue that the majority of government In India, the majority of marginalized sections are hospitals are providing free health services including tertiary deprived of quality secondary and tertiary healthcare ser- healthcare. Still, the majority of patients are spending a lot vices. The basic idea of introducing a new National Health of money from their pockets for their health needs. Hi-tech Protection Scheme is to provide cashless treatment to the facilities are not being offered by any government hospi- marginalized people in any government or private hospitals, tals including CT/MRI scans and other higher end services. including secondary and tertiary healthcare services. Earlier, Sometimes, required pathological laboratory and other diag- we had subcenters ahead of PHCs. Now, wellness centers will nostic services are available even in the urban-based sec- replace the subcenters, expecting a key role, especially in the ondary/tertiary care government hospitals. In this situation, rural parts of the country. Still, it is an unanswered question every patient should go to the private centers for diagnostic as to why people will not choose government hospitals for service, drugs and implants, according to the need. It is also their health needs over a period of time despite government better to note that all public hospitals charge a user fee for hospitals doing really well in some areas. Also, in India, peo- the major health issues, including heart, cancer care kidney, ple visiting the PHCs first would rather visit the secondary liver, etc.11 and tertiary healthcare centers directly for their various Health is highly unsure and changeable; moreover, it is simple health needs without any referral. It is a topic for the catastrophic to the poor families. Poor households not only study. In US/Europe, it is not possible, unless one has a strong spend huge money for their healthcare needs but also suf- referral from the lower healthcare facility.8 fer wage loss to get their health back. Some health experts If the people visit the PHCs immediately for their health have argued that this UHC scheme is not able to reduce cat- needs, the burden on the secondary and tertiary healthcare astrophic expenditure on the part of the patient. Hence, this will automatically be reduced. Keeping this in mind, the gov- is the time to doubly ensure effectively reducing catastrophic ernment has created wellness centers to provide primary expenditure through UHC. The UHC health benefit scheme healthcare education and services. Meanwhile, various state covers around Rs. 5 lakh which is sufficient to provide any governments also have introduced different health insur- type of healthcare /treatment in all types of hospitalization ance schemes that should not interfere with the Ayushman conditions. Moreover, this benefit package covers mostly

Bharat scheme which cause a kind of confusion among peo- every health condition that requires hospitalization, daycare, ple. There are some issues like the referral system. If anyone and surgeries, etc. The payment system has been designed wants to get benefits under the Aayushman Bharat scheme to cover all the costs, and the patient is not needed to pay in private hospitals, they must have the referral slip from anything from his/her pocket at any point of time. Health any government. hospital. Here, if the required service is not economists say the scheme is going to increase the cost available in the government hospital, only then should the of healthcare. However, the proposed UHC will consider- patient be given the referral slip to go to the higher medical ably manage the cost of health service by moving toward a center. This is not happening. Patients pay bribes to get refer- high-volume, low-margin model. Hence, UHC is a really good ral slips from government hospitals; sometimes, through scheme for the time being.12 political influence too. It shows people still do not have any Will Ayushman Bharat be affordable in the long run? The faith in government hospitals. This leads to having a kind of government should have brought this scheme long before, institutional corruption in the scheme.9 and it depends on the strong political will of the next gov- There is one more argument that this scheme is only ernment or available resource, or how much government is helpful to the insurance companies, enriching their profit. willing to spend in the future and. Several states have their However, this concern is a totally unestablished theory to ongoing healthcare schemes, and they are not showing date. It is found that most of the states are actually willing interest in joining the current Ayushman Bharat scheme, for to go with a legal trust mode, focusing on a high-volume, example, Delhi government. The scheme offers some special low-margin model. For insurance companies, there is a legal provisions to all the states like human resources, financial provision in the basic contract such that the insurance com- resources, state-of-the-art facilities, customizable technolog- panies can make 15% profit out of the total premiums.6 Due ical platforms, implementation systems, audit systems, and to heavy competition and nonprofit, insurance companies effective monitoring systems at no additional cost from the are asking for comparative premiums under UHC. Another state exchequer. It is generally agreed that we need to have question was the lack of supply to match the demand gen- strong information and communications (ICT) technology erated after implementing the UHC scheme. Experts opine because every beneficiary must get nationwide network hos- the new demand may be met through existing capacity with pitals if it is required for the healthcare system.5 the private sector in a more efficient manner or government If we focus exclusively on the primary healthcare sector, health institutes could need more infrastructure and man- then the burden on the secondary and tertiary healthcare power capacity soon.10 will be lessened. Not only hospitals but it will also be use- Quality is an essential contributor to the UHC efforts with ful to the family, mentally and financially. The ICT govern- stress on grounded technical work that can be contextualized ment must focus more on PHCs, so that any health issues can

Annals of the National Academy of Medical Sciences (India) Vol. 56 No. 4/2020 ©2020. National Academy of Medical Sciences (India). Universal Health Coverage in India Nanjunda 211 be solved if we diagnose it in an early stage. It is also found 5. Prices fixed by the government are far below market rate that the strategic purchasing pathway will be adopted to and it would be unsustainable to operate at such costs procure and pay for secondary and tertiary healthcare ser- while providing high-quality outcomes under UHC. The vices from public and private healthcare service providers. majority of private hospitals are not showing interest These two ideas have now been clubbed together in the to register under UHC, and they show interest to extend budget of 2018 to provide the required engine for the India’s medical treatment only in certain cases. Hence, the gov- big plan toward UHC. However, there are some experts who ernment needs to hike the rate, depending on the treat- opine ‘this scheme addresses the wrong problem or provide ment every year, and should have a realistic pricing a wrong solution even if it tends to address the right prob- mechanism in place. lem.” The government must opt for the public–private model 6. Since the referral letter is a must from the government (PPM) and that would be the best idea for the success of the hospital to get treatment in a private hospital under Ayushman Bharat scheme13 Ayushman Bharat–Arogya Karnataka, there is a chance for Health economists are of the opinion that the private sector prevailing more corruption and unnecessary delay. The in a UHC scheme is poorly regulated, and the government needs referral system must be cancelled if possible. Moreover, to focus on strengthening the obligate regulations on the part of critical procedures as announced by the government the private sector. The purchaser of the different health services under UHC need to be simplified. can play a vital role in making a system strong through their 7. Establishing a well-structured and well-organized refer- financial power over the private sector, and now the govern- ral system in the rural and tribal areas, providing com- ment is required to focus on the following segments of the UHC: prehensive services on the concept of primary health is required, so that the burden on secondary and tertiary 1. Setup price system effectively. healthcare may be minimized. 2. The proper establishment of the price regulatory 8. This is the time to focus on time surveillance of “at risk” mechanism. and “highly vulnerable sections” for various communica- 3. Focusing on the quality of health services. ble diseases like diabetes, BP, and cancer. 4. An incentive to the government hospital to improve 9. Proposal to outsource monitoring, empanelment, set- quality. tling of claims, grievance redressal—all vital functions of 5. Using electronic data sharing system with the help of a UHC—to commercial companies needs a new way out. information technology.14 10. Separate institutional mechanism required at the district

The UHC should be based on the PPM system. Moreover, it and state levels to oversee the program, with a new health ought to be noted that the government should not use its lim- system approach bringing all stakeholders together. ited financial and human resources to improve health services 11. Need to retain focus on increasing government invest- through the private sector. This idea may not be good for the ment on health, and there is a need to raise new resources Indian health system and budget. Private people can make their including CSR fund to meet the huge cost of UHC. presence felt in a UHC system, but their concentration will be 12. There must be a special provision for cancer and road only toward the profit motive. Determine understanding and accident patents in UHC. the part of both the government and private sector, so that 13. The unifying framework should be provided, so that the private sector should make use of their capacity, skill, and actions at all levels and by all stakeholders are mutually financial issues in providing quality service to the marginalized supportive. sections of the society. The private sector in health healthcare 14. India must invest in addressing inequalities in access to issues is required for their well-organized and capable network. health services and reducing reliance on out-of-pocket They must go for reasonable prices and be dictated by service (OOP) payments, and action is needed to improve regu- motives.15 latory framework and mediatory mechanisms if it is to achieve UHC by 2030. Policy Outcome 15. Comprehensive improvement in all health system build- 1. UHC should be treated like “one nation, one scheme.” ing blocks, such as financing, governance, and human 2. After implementing UHC, the workload has been mount- resources, should be planned and operationalized for ing on the existing hospital staff in all government hos- UHC. pitals. Hence, empowerment of government hospitals in 16. Engage the private sector in the provision of primary care terms of quality, infrastructure, drugs, and modern facility influence of medical audits to improve quality of care, is the need of the hour for the success of the UHC program. use costing studies to inform evidence-based provider 3. The disparity in the quality of healthcare services in the payment policy and data analytics to monitor provider public and private sector is continuing and the regulatory payment systems, and ensure quality of care is need of standards are neither established nor enforced correctly the hour. by the government agencies. 17. Existing village and health sanitation committees should 4. Outpatient visits, which constitute a bigger part of out be transformed into actively participating in health coun- of pocket expenditure, should be included in Ayushman cils. The role ofPanchayat Raj institutions in rural areas Bharat. and local bodies in urban areas are very vital in this scheme.

18. Governments and nongovernmental organizations, like Tentative Conclusion health professional associations and national health soci- eties, should be encouraged to contribute to the imple- The most common critique against the Ayushman Bharat mentation of the UHC process by integrating risk factor scheme is that the government is not stressing more on pre- control in their health sector strategies for certain com- ventive and promotive care. However, the real and tough mon health issues. challenge is how to provide both preventive and curative 19. The National Health Regulatory and Development at the same time. Also, we need to focus on growing cata- Authority (NHRDA), which regulates and monitors pub- strophic health expenditure among the poor people. In India, lic and private healthcare providers, must be given more normally, people will give up needy treatment because of powers and autonomy. the cost factor. People sell their movable and immovable (Sources: Proceedings of the National Academy of Medical properties just because of medical reasons, putting them Sciences Funded National Workshop on UHC held at Mysore into a cycle of poverty. Hence, the experts opine that the University (India) on June 19 and 20, 2019). state should focus more on curative aspects to minimize the burden on the universal healthcare programs.17 Moreover, it is also very important to bring strong government plan- Remarks ning to involve citizens regarding health behavior change The unifying framework for the UHC should be provided, so through health communication and evidence-based health that actions at all levels and by all stakeholders are mutually governance. Introducing prevention-based health checkups supportive, Governments and nongovernmental organizations, in every government health facility is the need of the hour. health professional associations, etc. should be encouraged to There is a need for a well-organized referral system in the contribute to the implementation of the process by integrating rural areas, providing complete services and focusing on risk factor control in their health sector strategies. Multisectoral primary healthcare. A well-structured system for occupa- action is necessary at all stages, because many preventive risk tional health diseases and the introduction of the concept of 18 factors lay outside the direct influence of the health sectors. occupational healthcare providers is also a must. We need Other departments and agencies whose work touches on pre- quality mass surveillance of “at risk” and “vulnerable popu- ventive care must also be mobilized (e.g., customs and excise, lations” for some life-threatening diseases like cancer, heart, trade and commerce, agriculture, law and justice, labor, trans- hypertension, and diabetes on an urgent basis. More impor- port and public services, education, and the environment).18 tantly, geographical coverage for endemic diseases are the

The key need of concern in fulfilling the aim of UHC includes need of the hour. a well-structured financing model for quality healthcare delivery; good training for senior health staff in public health insti- Conflict of Interest tutes; good package and the cost of healthcare interventions; None declared. and increasing state budget allocations for public health. While substantial applied research and findings are available today References regarding our journey toward UHC, sensible information to 1 WHO.The World Health Report 1998 Life in the 21st Century: address widespread constraints and support the planned policy, A vision for all. Available at: https://www.who.int/whr/1998/ decision touching health policies remain an area with incom- en/. Accessed June 3, 2020 plete insights. Eventually, India needs sensible solutions to 2 Karan A, Yip W, Mahal A. Extending health insurance to the move quantifiable development regarding UHC, and the general poor in India: An impact evaluation of Rashtriya Swasthya population thinks there’s no better.16 Bima Yojana on out of pocket spending for healthcare. Soc Sci Med 2017;181:83–92 3 Preker AS, The introduction of universal access to health Future Research—Must Focus On care in the oecd: lessons for developing countries. In: S. Nitagyarumphong and A. Mills, eds. Achieving Universal 1. Reveal the organization, financing, management, and Coverage of Health Care. Bangkok: Ministry of Public Health, resources to deliver universal healthcare services in India. 1998:103–124 2. Study on health and wellness centers and national health 4 Sengupta A, Creating, reclaiming, defending: non-commercialized protection schemes under UHC. alternatives in the health sector in Asia. In: McDonald D, Ruiters 3. Identify the issues and challenges to achieve UHC in the G, eds. Alternatives to Privatization: Public Options for Essential country. Services in the Global South. New York: Routledge Press, 2012:202–204 4. Impact of universal healthcare services on promotive, 5 Zodpey S, Farooqui HH. Universal health coverage in India: preventive curative, and rehabilitative health issues, espe- Progress achieved & the way forward. Indian J Med Res cially for the rural and tribal sections. 2018;147(4):327–329 5. Possible drivers of present health inequities within UHC 6 Rahman MM, Karan A, Rahman MS, et al. Progress toward uni- efforts, and possible approaches to shifting the curve versal health coverage: a comparative analysis in 5 South Asian toward proequity strategies Countries. JAMA Intern Med 2017;177(9):1297–1305

7 Sharma A, Ladd E, Unnikrishnan MK. Healthcare inequity and 13 Mekoth N, Dalvi V. Does quality of healthcare service deter- physician scarcity: Empowering non-physician healthcare. mine patient adherence? Evidence from the primary health- Econ Polit Wkly 2013;48(13):112–117 care sector in india. Hosp Top 2015;93(3):60–68 8 Wagstaff A. Reflections on and alternatives to WHO’s fairness of 14 Yellaiah J. Health insurance in India: Rajiv Aarogyasri health financial contribution index. Health Econ 2002;11(2):103–115 insurance scheme in Andhra Pradesh. IOSR Journal of 9 Mackintosh M, Channon A, Karan A, Selvaraj S, Cavagnero Humanities and Social Science 2013;8(1):7–14 E, Zhao H. What is the private sector? Understanding pri- 15 De Costa A, Diwan V. ‘Where is the public health sector?’ Public vate provision in the health systems of low-income and and private sector healthcare provision in Madhya Pradesh, middle-income countries. Lancet 2016;388(10044) :596–605 India. Health Policy 2007;84(2-3):269–276 10 National Health Policy. Available at: http://www.cdsco.nic.in/ 16 Chokshi M, Patil B, Khanna R, et al. Health systems in India. writereaddata/National-Health-Policy.pdf. Accessed June 3, J Perinatol 2016;36(s3):S9–S12 2019 17 Berman P. The impoverishing effect of healthcare payments 11 Keshri VR. Subodh Sharan Gupta Ayushman Bharat and road to in India: new methodology and findings. Econ Polit Wkly universal health coverage in India. Journal of Mahatma Gandhi 2010;45(16):65–71 Institute of Medical Sciences 2019;24(2):65–57 18 Ellis R, Alam M, Gupta I. Health insurance in India: prognosis 12 Press Information Bureau, Government of India. Cabinet and prospects. Econ Polit Wkly 2000;35(4):207–217 Approves Ayushman Bharat-National Health Protection Mission. 19 Prinja S, Kaur M, Kumar R. Universal health insurance in India: Available at: http://www.pib.nic.in/newsite/PrintRelease.aspx? ensuring equity, efficiency, and quality. Indian J Community relid=177816. Accessed March 27, 2018 Med 2012;37(3):142–149

THIEME 214 PerceptionOriginal Article and Satisfaction on the Health Care System Al-Kalbani et al.

Public’s Perception and Satisfaction on the Health Care System in Sultanate of Oman: A Cross-Sectional Study

Humaid Al-Kalbani1 Tariq Al-Saadi2,3 Ahmed Al-Kumzari4 Hassan Al-Bahrani4

1Department of Ophthalmology, Al-Buraimi Hospital, Ministry of Address for correspondence Tariq Al-Saadi, MD, Department Health, Sultanate of Oman of Neurosurgery, Khoula Hospital, Muscat, Sultanate of Oman; 2Department of Neurosurgery, Khoula Hospital, Muscat, Sultanate Department of Neurology and Neurosurgery, Montreal Neurological of Oman Institute-McGill University, 3801 Montreal, Canada 3Department of Neurology and Neurosurgery, Montreal (e-mail: [email protected], [email protected]). Neurological Institute-McGill University, Montreal, Canada 4Department of Pediatric, Sultan Qaboos University Hospital, Oman Medical Speciality Board, Muscat, Sultanate of Oman

Ann Natl Acad Med Sci (India):2020;56:214–219

Abstract Objective There are no “gold standard” parameters to measure patient satisfaction regarding the health care system provided by the government. Most of the developed countries have well-structured health care systems, and they depend on patient satisfaction to evaluate and optimize performance and activities of such systems. The study was conducted to evaluate the Omani population’s satisfaction toward public and private health care systems existing in the country. Materials and Methods A cross-sectional study was conducted with a predesigned

and pretested questionnaire that was sent to all regions of the Sultanate of Oman via an electronic link. The questionnaire included 22 questions divided into two sections: (1) public and private health care systems in Oman, and (2) abroad treatments. Results The response rate of the 11 Oman’s governorates was 73.9%. There was an association between gender, age, marital status, and the level of education with the preference for local private hospital’s treatment (p < 0.001). Both males (88.1%) and females (83.9%) preferred to be treated by Omani doctors. The association between gender and the preference to be treated by the Omani doctors was statistically significant (p = 0.016). There was a significant relationship between the overall patient Keywords satisfaction regarding the treatment that they received and all of the following param- ►►health care system eters: well-trained nurses, competency of doctors, professional behavior, and skill level in Oman of the staff. On the other hand, 88% of the participants were unhappy about appoint- ►►population ment waiting times to be seen in the tertiary-care hospital. satisfaction Conclusion The study showed that most of the participants have preferred to be ►►public hospital treated by Omani physicians and nurses, however, hospitals need to make operational ►►private hospital and working changes in order to decrease the appointment waiting time, as this was ►►treatment abroad found to be one of the most common reasons for population dissatisfaction.

DOI https://doi.org/ © 2020. National Academy of Medical Sciences (India). 10.1055/s-0040-1721554 This is an open access article published by Thieme under the terms of the Creative ISSN 0379-038X. Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/). Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India Perception and Satisfaction on the Health Care System Al-Kalbani et al. 215

Introduction include any personal information about the participant so that they can feel assured about their privacy and answer In the last few years, the competition for providing the best the questions freely and honestly. All participants signed a 1 medical services increased worldwide. Nowadays, patient consent prior to filing up the questionnaire. After all partici- satisfaction regarding governmental or public health care sys- pants answered and completed the questions, the question- tems considered one of the best indicators for measuring the naire forms were dispatched back to the sender’s address. quality of health care system, as still there are no “gold stan- The received questionnaire forms were then perused, data 2 dard” parameters to measure patient satisfaction. Patients’ recorded, and the percentages of each answered question satisfaction is the extent to which service seekers feel happy were documented. The collected information was analyzed Address for correspondence Tariq Al-Saadi, MD, Department with their health care, both inside and outside of physician/ by using the SPSS program. of Neurosurgery, Khoula Hospital, Muscat, Sultanate of Oman; surgeon’s office. It is a measure of quality of service provid- Department of Neurology and Neurosurgery, Montreal Neurological ers insights into various aspects of medicine, including the Institute-McGill University, 3801 Montreal, Canada effectiveness of their care and the received empathy. Most Results and Discussion (e-mail: [email protected], [email protected]). of the developed countries having well-structured health This study was conducted in the Sultanate of Oman in order care systems depend on patient satisfaction to evaluate the to consider and use the results to improve service quality and qualities of the provided services by their health care facil- patient satisfaction from the provided services in the hospital 3 ities. Understanding patient needs by both obtaining the environment in Oman. This is the first study to be conducted service seekers feedback toward the offered services and in the country to investigate the satisfaction of the Omani cit- establishing good communication between the patient and izens toward health care services. Prior researches from other the physician, where their attitude and behavior, availability countries suggested that the health service quality provided to of services technology, and hospital-facilitated conveniences the population of the nation has a significant relationship with to the patient placed a major role in patient’s satisfaction patients satisfaction.8,9 As the quality of health care services 4 with some other minor factors. In 2016, the United States improves in a country, the patients are going to feel reassured, spent nearly 18% of its gross domestic product (GDP around not only to seek curative services within the country but also 21.43 trillion U.S. dollar in 2019) on health care, whereas services that are preventive in nature.10 The assessment of ser- the next highest comparable country (Switzerland, GDP vices’ quality pose some interesting challenges, which have around 1566.23 billion U.S. dollar in 2019) devoted less than engaged academics and practitioners in the developed coun- 5 13% to this category. Oman is considered as having one of tries for quite some time now. In the past, the health care qual-

the best health care systems in the world according to World ity was assessed and defined by clinicians in terms of technical 6 Health Organization reports. However, Omani Ministry of delivery of care.10 There was a lack of patient’s perspective in Health (MOH) expenditures are less than 6.1% (1816.88 mil- determining the quality. Recent literatures show the impor- lion U.S. dollar) of its GDP and that is due to the availabil- tance of other factors, including health insurance, administra- ity of a good feedback mechanism for obtaining the patient tive policies, and community groups, which may influence the satisfaction through a hotline system, where the MoH gives satisfaction of patients toward the provided health care facili- priority to evaluation of health care services and get patients’ ties.11 Other investigators in this area believe that patient’s per- 7 feedback. spective represents the most important aspect in terms of the In the present study, a cross-sectional feedback was quality of health care service delivery.11 obtained by distributing a survey questionnaire to all Oman Out of 1,575 patients who received the questionnaire from regions in order to get general ideas from Omani citizens all 11 governorates regions of Oman, total 1,164 completed about the quality of health care system and on the services all the questions in the survey (73.9%). The responses accord- offered by the health care providers all over the country. ing to the age groups were divided into three categories: less than 25 years (15.5%), between 25 and 50 years (80.3%), and more than 50 years (4.2%) with male to female ratio 1.5:1.0. Materials and Methods The distribution of participants in the survey almost reflects This study was conducted through a questionnaire distrib- the normal population of the governorate, except for Dhofar uted to all regions of the Sultanate of Oman from February governorate which has a high population and a low number 12 to February 16, 2019 via an electronic link. Related of participants (►Table 1). The highest number of partici- studies to this research were reviewed, then questionnaire pants were male between the age of 25 and 50 years, which was formulated, and translated into the Arabic language. is corresponding with the natural geographic distribution of Participant’s age, gender, marital status, and living region Omani population (66% males and 34% females with a mean were obtained. The questionnaire included 22 questions. In age of 36 years).12 addition to personal demographic information, the ques- Participants who received treatments in government or pub- tionnaire also targeted information on educational status of lic hospitals were 98%, and those received treatments in local the participants. The questionnaire has two main sections: private hospitals were 77.4%. The association between gender, (1) public and private health care systems in Oman, and age, marital status, levels of education, and treatments in local (2) abroad treatments. Section (1) mainly consists of “yes or private hospitals were statistically significant (►Tables 2 and 3 ). no” type of answers, whereas section (2) consists of “agree Those who received treatments locally in the public or pri- and disagree” type of questions. The questionnaire did not vate hospitals preferred to be treated by Omani nurses with

Annals of the National Academy of Medical Sciences (India) Vol. 56 No. 4/2020 ©2020. National Academy of Medical Sciences (India). 216 Perception and Satisfaction on the Health Care System Al-Kalbani et al.

Table 1 Comparison between population distribution and participation for each governorates Governoratesa Population13 % Participant % Muscat 528,327 21.1 311 20.3 Dhofar 210,984 8.4 25 1.6 Musandam 28,477 1.1 63 4.1 Al Buraymi 54,818 2.2 80 5.2 Al Dakhliyah 343,712 13.7 210 13.7 Al Batinah North 490,332 19.6 309 20.2 Al Batinah South 298,649 11.9 308 20.1 Ash Sharqiyah South 201,783 8.1 71 4.6 Ash Sharqiyah North 173,113 6.9 58 3.8 Al Dhahirah 151,308 6.0 85 5.6 Al Wusta 23,866 1.0 11 0.7 Total 2,505,369 100 1,575 100 aStatistic from National Center for Statistic and Information, statistical yearbook 2018.

Table 2 The association between gender and age and receiving treatment in private hospitals Treated in private Gender (%) Age (%) hospital Male Female <25 25–50 >50 Yes 688 (79.4) 415 (74) 264 (85) 866 (76.6) 43 (75.4) No 179 (20.6) 146 (26) 47 (15) 264 (23.4) 14 (24.6) Total 867 (100) 561 (100) 311 (100) 1,130 (100) 57 (100) p-value 0.023 <0.001

Table 3 The association between level of education, marital status with receiving treatment in private hospitals Treated Marital status (%) Level of education (%) in private Single Married Divorced Less than High University Diploma Bachelors Master PhD hospitals high school school student Yes 248 (65.1) 848 (81.9) 7 (63.6) 34 (66.7) 346 (70.5) 133 (71.1) 137 (85.1) 364 (83.1) 69 (86.25) 20 (100) No 133 (34.9) 188 (18.1) 4 (36.4) 17 (33.3) 145 (29.5) 54 (28.9) 24 (14.9) 74 (16.9) 11 (13.75) 0 Total 381 (100) 1,036 (100) 11 (100) 51 (100) 491 (100) 187 (100) 161 (100) 438 (100) 80 (100) 20 (100) p-value <0.001 <0.001

Table 4 The association between gender and the preference The data revealed that most of the population received to be treated by Omani doctors treatments by the government or local public hospitals Gender Prefer to be treated by Omani doctor more than the private hospitals. This reflects the good qual- Yes No Total ity of health services provided by the government hospitals in Oman. Similar conclusions were drawn by previous Female 501 (84%) 96 (16%) 597 (100%) researches in Malaysia concluded that countries with non- Male 800 (88.1) 108 (11.9) 908 (100%) satisfactory quality of services in the public hospitals led to Total 1,301 204 1,505 greater use of private providers.16 p–value 0.015 On the scale of 0 to 10 (where 0 denotes: poor and 10 denotes: excellent quality of health care), 64.1% of the a percentage of 78%. Also, both males (88.1%) and females participants gave a score of 5 or above for their perception (83.9%) preferred to be treated by Omani doctors. The associ- of the quality of general health services in government hos- ation between gender and preference to be treated by Omani pitals (►Fig.1). Most of the participants were unhappy (88%) doctor was statistically significant (p = 0.016; ►Table 4). The regarding to the appointment waiting time (►Fig. 2). The previous studies showed that patients are able to evaluate waiting time to get an appointment in tertiary care hospi- the doctor’s and nurse’s skills when they are dealing with tals according to participants experiences vary between patients.14,15 less than 1 month to more than 4 months as shown in

Fig. 1 Participants satisfaction scale of the general health services provided in the public hospitals.

Fig. 3 The preferable destinations for abroad treatment for Omani Fig. 2 Patients satisfaction regarding hospital appointments. patients.

Table 5 The average waiting time to get an appointment in The preferable destinations for abroad treatment for Omani tertiary hospitals according to the participants experiences patients were hospitals/health care facilities located in India, Duration Frequency Percentage Germany, Thailand, Iran, the Gulf Cooperation Council coun- Less than 1 mo 65 4% tries, and North America (►Fig. 3). A previous cross-sectional 1–2 mo 350 23% study, which was conducted in the Al Dakhilya region of the Sultanate of Oman, showed that Thailand (50%) was the first 2–4 mo 519 35% destination followed by India (30.0%), Iran (10.0%), Bahrain More than 4 mo 535 36% (7.5%), and United Arab Emirates 2.5%. The postulated rea- Not mentioned 35 2% son for such a perception is due to the fact that the cost of Total 1,504 100% medical care is less in South Asian countries. Another study done in Saudi Arabia had shown that patients, who traveled ►Table 5. When compared the data of the present study abroad for renal transplantation, went to Pakistan (49%) fol- with that of a previous study, it was observed that there lowed by the Philippines (28%), Egypt (11%), and the United was a relationship between patient satisfaction with wait- States (3.2%).18 ing time, and the patient in outpatient situation perceives Couple of reasons for the Omani patients to travel abroad the long waiting time spent to reach the consultant’s room were revealed in the study including the long waiting time in as not satisfied and that in turn will affect their behavior the local hospitals (52.2%), lack of confidence in the health accordingly.17 services provided in Oman (45%), high quality of health care In the “travel abroad section,” more than a half of the abroad (41%), unavailability of the treatments locally (30.5%), participants preferred to be treated abroad (58.8%) as com- combining treatments with relaxing holidays (11.5%), cost- pared to those who availed health care local hospitals in competitive advantages (10%), and others. In a previous Oman (54.5%). Though not statistically significant, more of study, Al-Hinai reported that 15% of the participants did the participants traveled abroad for treatments or checkups. not even seek any medical care locally, but rather traveled

Annals of the National Academy of Medical Sciences (India) Vol. 56 No. 4/2020 ©2020. National Academy of Medical Sciences (India). 218 Perception and Satisfaction on the Health Care System Al-Kalbani et al.

Table 6 The association between gender, age, and level of education with the efficiency of service received in hospitals Services are Gender (%) Age (%) provided Male Female <25 y 25–50 y >50 y efficiently Disagree 524 (59.3) 312 (53.1) 112 (49.6) 698 (58.9) 26 (43.3) Agree 359 (40.7) 276 (46.9) 114 (50.4) 487 (41.1) 34 (56.7) Total 883 (100) 588 (100) 226 (100) 1,185 (100) 60 (100) p–value 0.028 0.001

Table 7 The association between level of education and efficiency of serves received in hospitals Services are Level of education (%) provided Less than High school University Diploma Bachelors Master PhD efficiently high school student Disagree 23 (42.6) 297 (60) 101 (53.2) 96 (58.2) 260 (56.4) 45 (9.3) 14 (66.7) Agree 31 (57.4) 198 (40) 89 (46.8) 69 (41.8) 201 (43.6) 440 (90.7) 7 (33.3) Total 54 (100) 495 (100) 190 (100) 165 (100) 461 (100) 485 (100) 21 (100) p–value 0.182

Table 8 Association between skilled staff and doctors and doctors communication and information providing to the patient about the participant’s condition Doctors are willing to Usually given adequate Usually given adequate answer any questions information on my information on my health treatment condition Hospitals are having skilled <0.001 <0.001 <0.001 staffs

Table 9 The association between the overall satisfaction and staff and services provided in the hospitals The nurses The staffs are Services are The hospitals are The doctors are are well professional provided having skilled competent trained efficiently staffs Overall satisfied <0.001 <0.001 <0.001 <0.001 <0.001 with the treatment received at the hospitals

abroad directly without specific explanations.2 This study and all of the followings: well-trained nurses, competent doc- also showed that dissatisfaction with local treatments was tors, and professional and skilled staff (p < 0.005; ►Table 9). reported to be responsible for only 5.9% cases who travelled The present study is a preliminary investigation and has to foreign countries for seeking the medical care.2 The same limited generalization. Further additional researches are study reported that 85% of the Omani participants traveled needed with further validation of the questionnaire, specif- abroad to get treatments only, 10% for both treatments and ically by including more health/medical care variables. It is tourism, and 2.5% for a health and medical check-up. important that patient-driven quality standards should be Most of the participants agreed that hospitals have skilled investigated in depth, and addressed more in order to enable staff (68.3%). However, only 43.1% of the participants were of service providers to further improve their quality of services. the view that the medical care and services were provided efficiently with a statistically significant association with age Conclusion and the levels of education, but not with gender of participants as showing in ►Tables 6 and 7. In order to achieve a competitive advantage, both govern- ►Table 8 shows the significant relationship between the ment and private hospitals must keep improving their ser- willingness of doctors to answer the patients’ questions and vices on a longitudinal and continuous basis to ensure that providing adequate information on their health conditions/ the quality of service provided are at the maximum level to treatment and between the efficacy of health care. There was gain a patient’s optimum satisfaction, and to have an impact a significant relationship between the overall patient’s satis- on patient’s future behavioral perceptions. Important infer- faction from the treatments received at the attending hospital ences of the present study are that the majority of Omanis

Annals of the National Academy of Medical Sciences (India) Vol. 56 No. 4/2020 ©2020. National Academy of Medical Sciences (India). Perception and Satisfaction on the Health Care System Al-Kalbani et al. 219 prefer to be treated by Omani doctors. Hospitals need to private healthcare delivery. Int J Public Sector Management make new changes in order to decrease appointment’s wait- 2010;23(3):203–220 ing time, as this was found to be one of the most common 9 Kessler DP, Mylod D. Does patient satisfaction affect patient loyalty.? Int J Health Care Qual Assur 2011;24(4):266–273 reasons for population’s dissatisfactions. 10 Andaleeb SS. Determinants of customer satisfaction with hospitals: a managerial model. Int J Health Care Qual Assur Inc Conflict of Interest Leadersh Health Serv 1998;11(6-7):181–187 None declared. 11 O’Connor SJ, Shewchuk RM, Carney LW. The great gap. Physicians’ perceptions of patient service quality expectations References fall short of reality. J Health Care Mark 1994;14(2):32–39 12 “ World Population Prospect- Population Division. “ United 1 Trinh LN, Fortier MA, Kain ZN. Primer on adult patient satisfac- Nations, United Nations. Available at: population.un.org/wpp/. tion in perioperative settings. Perioper Med (Lond) 2019;8:11 Accessed 2019 2 Al-Hinai SS, Al-Busaidi AS, Al-Busaidi IH. Medical tourism 13 National Center for statistic and information, statistical abroad: a new challenge to Oman’s health system - Al Dakhilya Yearbook, Page no.79, 2018, Oman. Available at: https:// region experience. Sultan Qaboos Univ Med J 2011;11(4): onlinelibrary.wiley.com/doi/pdf/10.1002/9780470713518. 477–484 fmatter. Accessed 2018 3 Bleich SN, Ozaltin E, Murray CK. How does satisfaction with 14 Amin M, Isa Z, Fontaine R. The role of customer satisfaction in the health-care system relate to patient experience? Bull enhancing customer loyalty in Malaysian Islamic banks. Serv World Health Organ 2009;87(4):271–278 Ind J 2011;31:1519–1532 4 Boissy A, Windover AK, Bokar D, et al. Communication skills 15 Manaf NHA. Patient satisfaction in outpatient clinics of training for physicians improves patient satisfaction. J Gen Malaysian public hospitals. IIUM Journal of Economics and Intern Med 2016;31(7):755–761 Management 2006;14(1):81–110 5 OCED. OECD Health Statistics 2018. 2018. Available at: http:// 16 Alghamdi SA, Nabi ZG, Alkhafaji DM, et al. Transplant tour- www.oecd.org/els/health-systems/health-data.htm. Accessed ism outcome: a single center experience. Transplantation August 20, 2018 2010;90(2):184–188 6 The World Health Report 2000 (Health Systems: Improving 17 Goel S, Sharma D, Singh A. Development and validation of a Performance). WHO Geneva. Available at: https://www.who. patient satisfaction questionnaire for outpatients attend- int/whr/2000/en/. Accessed 2000 ing health centres in North Indian cities. J Health Serv Res 7 MOH annual health report, Chapter Two: Health Status Policy 2014;19(2):85–93 Indicators, Page No.2 - 3, 2018 Oman. Available at: https:// 18 Hwang J, Vu GT, Tran BX, et al. Measuring satisfaction with www.moh.gov.om/en/web/statistics/-/20-60. Accessed 2018 health care services for Vietnamese patients with cardiovas- 8 Owusu-Frimpong N, Nwankwo S, Dason B. Measuring ser- cular diseases. PLoS One 2020;15(6):e0235333

vice quality and patient satisfaction with access to public and

THIEME 220 ThoracoscopicOriginal Article Congenital Diaphragmatic Hernia Repair Pandey, Gopal

Congenital Diaphragmatic Hernia: Experience and Results of Thoracoscopic Repair from a Tertiary Care Hospital

Vaibhav Pandey1 Saroj C. Gopal1

1Department of Pediatric Surgery, Institute of Medical Sciences, Address for correspondence Vaibhav Pandey, MS, MCh, Banaras Hindu University, Varanasi, Uttar Pradesh, India Department of Pediatric Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India (e-mail: [email protected]).

Ann Natl Acad Med Sci (India):2020;56:220–223

Abstract Introduction Congenital diaphragmatic hernia (CDH) is one of the most common congenital anomalies encountered by pediatric surgeons. With the advances in the pediatric minimal access surgery, its role in the repair of CDH has also increased. We have been using thoracoscopy for the repair for CDH since 2015. We herein report our experience of CDH repair in newborns. Materials and Methods A retrospective review was conducted from July 2015 to December 2019 in the Department of Pediatric surgery after ethical approval from the institutional review board and included all the children with CDH who underwent thoracoscopic repair. The case records were used to assess the demographic details, type of defect, and early and late postoperative complications of thoracoscopy in CDH. Results Thoracoscopic repair was attempted in 29 patients of CDH. Eight (27.5%) patients converted to open procedure and were excluded from the study. Primary closure of the diaphragmatic defect was performed in 90.4% (19) patients. Also, 9.5% (2) children required mesh repair. There was no intraoperative death. Postoperative ventilation was Keywords required in 57.1% (12) children. The mean time on the ventilator was 3.03 ± 0.9 days. The ►►congenital mean age of children requiring postoperative ventilation was less compared with children diaphragmatic hernia who were extubated in the postoperative period (p = 0.032). The median follow-up in our ►►thoracoscopy study was 12 months and 28.5% of patients developed recurrence of the diaphragmatic ►►pediatric age hernia. All the children underwent laparotomy and repair of the diaphragmatic defect. ►►minimal access Conclusion Thoracoscopic repair is a safe and effective option for the repair of CDH surgery in children performed by surgeons with significant procedure experience.

Introduction complications with open surgery like adhesive obstruction and multiple interventions in cases with complication or Congenital diaphragmatic hernia (CDH) is one of the most recurrence adds to long-term morbidity and mortality. The common congenital anomalies encountered by pediatric minimal access surgery has shown a better outcome with surgeons. The advances in neonatal management and fetal respect to these complications. With the advent of pedi- intervention have decreased the overall mortality, but still, atric minimal access surgery, its use in the CDH repair has the mortality is high in cases with poor prognosis.1,2 With also increased. Early reports have shown a decreased mor- improving overall survival, the long-term morbidity and bidity and improved long-term outcome with the thoraco- mortality have also come into the picture.3 Early and late scopic repair of CDH.4,5 Different authors have reported their

DOI https://doi.org/ © 2020. National Academy of Medical Sciences (India). 10.1055/s-0040-1714200 This is an open access article published by Thieme under the terms of the Creative ISSN 0379-038X. Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/). Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India Thoracoscopic Congenital Diaphragmatic Hernia Repair Pandey, Gopal 221 experiences with the variable outcome and a limited number of patients, especially the newborns.6,7 We have been using thoracoscopic repair for CDH repair since 2015. We herein report our experience of CDH repair in children.

Materials and Methods

A retrospective review was conducted from July 2015 to December 2019 at the department of pediatric surgery after ethical approval from the institutional review board and included all children with CDH who were repaired tho- racoscopically. The case records were used to assess the demographic details, type of defect, and early and late postoperative complications. The diagnosis was made by the X-ray chest in all the patients.

Operative Technique

We used the standard three-port technique for thoracoscopic repair of CDH. After endotracheal intubation, the Fig. 1 Posterolateral diaphragmatic defect with small bowel in patients were placed in lateral decubitus position and sta- hemithorax. bilized. Pneumothorax was created with the Veress needle, inserting it just below the scapular tip in the midaxillary line followed by carbon dioxide insufflation up to a pressure of 3 to 5 mm Hg. The Veress needle was replaced with 5-mm port for 30-degree telescopes. The herniating contents were visualized and gradually pushed into the abdomen with the telescope itself, under vision to create space. The pneumothorax helps in the reduction of contents into the abdomen. Following this partial reduction, the pressure is gradually increased to 5 to 6 mm Hg, and then two more 3-mm trocars are placed under vision in the anterior and posterior axillary line, just cephalad to camera port, utilizing maximum space to achieve the triangulation. However, the triangulation is not possible because of the limited space. After reducing the contents, the hernia defect was repaired using nonabsorb- able interrupted sutures (polyester 2/0 or polypropylene 2–0 or polyamide 2–0) encompassing two borders of the diaphragmatic muscle defect with intracorporeal knotting (►Figs. 1–3). The rim of the defect was sewn to the thoracic wall when adequate rim was not present. A chest drain was inserted in the lowest port posteriorly. It was withdrawn Fig. 2 Spleen in hemithorax as content of hernia. when the thoracic X-ray result was normal. 7.5 months (interquartile range: 4.0–10.6 months) months. Results Neonates presented with a history of respiratory distress at birth, while the older children presented with a history of During the study period, the thoracoscopic repair of CDH repeated chest infection, multiple hospital admissions, and was attempted in 29 cases. The conversion to open surgery failure to thrive. The hernia was located on the left side in was required in eight (27.5%) cases. All these cases were 19 patients and on the right side in 2 patients (►Table 1). managed by laparotomy via subcostal incision and repair We were able to close the defect primarily in 19 patients. of the diagrammatic defect was performed. The conversion In two patients, thoracoscopic mesh repair was performed. in six (75.0%) cases was done because of hemodynamic Plication of sac followed by repair was done in four cases instability. In two cases, the spleen could not be reduced with sac. The mean operative time was 92.3 ± 20.4 minutes due to congestion enlargement. So, there were 21 patients, and there was no significant blood loss in any of the cases. including 14 boys and 7 girls who underwent thoracoscopic A chest drain was inserted in all patients. There was no intra- repair of CDH. Nine (42.0%) cases were operated in the operative death. Postoperative ventilation was required in neonatal period. The median age of the other 12 cases was 12 (57.1%) children. The mean time on the ventilator was

Annals of the National Academy of Medical Sciences (India) Vol. 56 No. 4/2020 ©2020. National Academy of Medical Sciences (India). 222 Thoracoscopic Congenital Diaphragmatic Hernia Repair Pandey, Gopal

repair of CDH by Becmeur et al,8 different centers followed-up with their experience. The results were mixed. Multiple small studies showed thoracoscopic repair to be safe and effective for CDH with the better cosmetic outcome, decreased rates of adhesive obstruction in follow-up, and decreased pain in postoperative period.9,10 On the con- trary to these findings, other studies did not reveal any advantage of the thoracoscopic approach. Further, this was associate with an increased rate of recurrence11,12 with per- sisting concern about hypercapnia and acidosis.13 Most of the evidence available is in the form of small retrospective. But there is a growing concern about the thoracoscopic repair as the long-term data and larger studies are coming. One of the largest studies published by CDH study group has shown significantly higher recurrence rate with the thoracoscopic repair of CDH.14 The study examined data from 4,526 infants who had a CDH repair, of which 151 had minimally invasive repairs. The minimally invasive repairs had a 7.9 versus 2.7% recurrence rate for open, a statistically significant difference. In our series, we have an overall Fig. 3 Closed defect with interrupted Prolene 2–0 interrupted sutures. recurrence rate of 28.5%, which is very high compared with other series. But only one (9%) child had recurrence out of the last 11 cases. Also, 50% of the first 10 cases had a recur- Table 1 Demographic details of patients rence. As we have been through our learning curve, we have Characteristics (n = 21) managed to decrease the recurrence rates by adhering to a few principles. One of the important factors for a longer Age Neonatal 9 (42.8%) learning curve in pediatric patients is limited space. For bet- Postneonatal 12 (57.1%) ter manipulation of instruments and proper visualization

Gender Male 14 (66.6%) during an endoscopic procedure, trocars should be placed Female 7 (33.3%) in a triangular fashion. In children, especially in neonates, it Side Right 2 (9.5%) is very difficult to achieve because of the small size of the Left 19 (90.4%) thoracic cavity and the presence of ribs. This does not allow ideal port placement in most of the cases and makes the Repair Primary 19 (90.4%) handling of suture difficult.15 We have increased the num- Mesh repair 2 (9.5%) ber of sutures and thus decreased the gap. Further, we have Mean duration of surgery 92.3 ± 20.4 minutes started using mesh (polypropylene) in cases with larger gap and undue tension. Different long-term studies have proven the benefit of thoracoscopic repair in the positive outcomes 3.03 ± 0.9 days. The mean age of children requiring post- in terms of bowel obstruction. We also did not observe any operative ventilation was (24.0 ± 6.8 days) less than those case with adhesive obstruction in our series. The results who did not require ventilation in postoperative period were similar to other studies.14,16 There is significant long- (52.8 ± 13.9 days) (p = 0.032). Two children with ventilation term decrease in the number of admissions due to adhe- requirement died due to ventilator associate pneumonia sive obstruction, relaparotomies due to bowel obstruction, in the postoperative period. The mean postoperative hos- and overall mortality.6 Laparoscopic approach has also been pitalization was 7.4 ± 3.2 days. The median follow-up of advocated by different groups for the repair of CDH.8,17 But children was 12 months (range: 6–36 months). Six patients the laparoscopy is associate with difficulty in reduction of developed recurrence within one year of repair. All these the contents. Trauma while pulling the contents into the six children underwent laparotomy for the repair of the abdomen. Further, the pneumoperitoneum is against and diaphragmatic defect. pushes the contents back into the chest. Thoracoscopy provides all these advantages over the laparoscopy.18,19 The suturing is also difficult by laparoscopy approach as bowel Discussion comes and obscures the field. We present our series of tho- The management of CDH has undergone a sea change, racoscopic procedures for CDH repair during 4-year-period. from an earlier concept of immediate repair to the mod- Our study showed that thoracoscopic repair is safe and ern understanding of stabilization and delayed repair.1 The feasible for CDH in children and newborns. Our experi- understanding of the pathogenesis and prognostic factors ence is similar to other authors who have also experienced have led to a modification in the resuscitation and surgi- the improved efficacy rates of thoracoscopic repair with cal techniques. Following the first successful thoracoscopic experience.

Annals of the National Academy of Medical Sciences (India) Vol. 56 No. 4/2020 ©2020. National Academy of Medical Sciences (India). Thoracoscopic Congenital Diaphragmatic Hernia Repair Pandey, Gopal 223

Conclusion 8 Becmeur F, Jamali RR, Moog R, et al. Thoracoscopic treatment for delayed presentation of congenital diaphragmatic The outcome of thoracoscopic repair of congenital diaphrag- hernia in the infant. A report of three cases. Surg Endosc matic hernia depends on the competency of surgeon and 2001;15(10):1163–1166 their learning curve. It is a safe and effective option with 9 Lao OB, Crouthamel MR, Goldin AB, Sawin RS, Waldhausen JHT, Kim SS. Thoracoscopic repair of congenital diaphrag- excellent outcome in the hands of a competent surgeons. matic hernia in infancy. J Laparoendosc Adv Surg Tech A Authors’ Contributions 2010;20(3):271–276 10 Liem NT. Thoracoscopic approach in management of congenital S.C.G. contributed in study conception and design, draft- diaphragmatic hernia. Pediatr Surg Int 2013;29(10):1061–1064 ing the manuscript, and critical revision. V.P. contributed 11 Okazaki T, Okawada M, Ishii J, et al. Intraoperative ventilation in study conception and design analysis and data interpre- during thoracoscopic repair of neonatal congenital diaphrag- tation, data acquisition, and drafting of the manuscript. matic hernia. Pediatr Surg Int 2017;33(10):1097–1101 12 Huang JS, Lau CT, Wong WYY, Tao Q, Wong KK, Tam PKH. Conflict of Interest Thoracoscopic repair of congenital diaphragmatic hernia: None declared. two centres’ experience with 60 patients. Pediatr Surg Int 2015;31(2):191–195 13 Schneider A, Becmeur F. Pediatric thoracoscopic repair of con- References genital diaphragmatic hernias. J Vis Surg 2018;4:43 14 Tsao K, Lally PA, Lally KP; Congenital Diaphragmatic Hernia 1 Smith NP, Jesudason EC, Featherstone NC, Corbett HJ, Losty PD. Study Group. Minimally invasive repair of congenital dia- Recent advances in congenital diaphragmatic hernia. Arch Dis phragmatic hernia. J Pediatr Surg 2011;46(6):1158–1164 Child 2005;90(4):426–428 15 von Renteln D, Vassiliou MC, Rösch T, Rothstein RI. 2 Friedmacher F, Pakarinen MP, Rintala RJ. Congenital dia- Triangulation: the holy grail of endoscopic surgery? Surg phragmatic hernia: a scientometric analysis of the global Endosc 2011;25(5):1355–1357 research activity and collaborative networks. Pediatr Surg Int 16 Shah SR, Wishnew J, Barsness K, et al. Minimally invasive con- 2018;34(9):907–917 genital diaphragmatic hernia repair: a 7-year review of one 3 Leeuwen L, Fitzgerald DA. Congenital diaphragmatic hernia. institution’s experience. Surg Endosc 2009;23(6):1265–1271 J Paediatr Child Health 2014;50(9):667–673 17 He Q, Zhong W, Wang Z, Yan B, Xie X, Yu J. Simple and safe 4 Tyson AF, Sola R Jr, Arnold MR, Cosper GH, Schulman AM. thoracoscopic repair of neonatal congenital diaphragmatic Thoracoscopic versus open congenital diaphragmatic hernia hernia by a new modified knot-tying technique. Hernia repair: single tertiary center review. J Laparoendosc Adv Surg 2019;23(6):1275–1278 Tech A 2017;27(11):1209–1216 18 Fujishiro J, Ishimaru T, Sugiyama M, et al. Minimally invasive

5 Jain V, Agarwala S, Bhatnagar V. Recent advances in the man- surgery for diaphragmatic diseases in neonates and infants. agement of congenital diaphragmatic hernia. Indian J Pediatr Surg Today 2016;46(7):757–763 2010;77(6):673–678 19 Vijfhuize S, Deden AC, Costerus SA, Sloots CEJ, Wijnen RMH. 6 Gomes Ferreira C, Reinberg O, Becmeur F, et al. Neonatal min- Minimal access surgery for repair of congenital diaphragmatic imally invasive surgery for congenital diaphragmatic hernias: hernia: is it advantageous?–An open review. Eur J Pediatr Surg a multicenter study using thoracoscopy or laparoscopy. Surg 2012;22(5):364–373 Endosc 2009;23(7):1650–1659 7 Barroso C, Correia-Pinto J. Thoracoscopic repair of congenital diaphragmatic hernia: review of the results. Minerva Pediatr 2018;70(3):281–288

THIEME .HandlingOriginal Article of Cadavers in Mortuary Amidst COVID-19 Pandemic Gupta et al 224

Handling of Cadavers in a Mortuary amidst COVID-19 Pandemic

Rimpi Gupta1 Deepak Goyal2 Virendra Budhiraja1 Shveta Swami1 Swati Bansal1 Neha Gaur1

1Department of Anatomy, Kalpana Chawla Government Medical Address for correspondence Rimpi Gupta, MBBS, MS, Department College, Karnal, Haryana, India of Anatomy, Kalpana Chawla Government Medical College, Karnal, 2Department of Forensic Medicine and Toxicology, Bhagat Phool Haryana 132001, India (e-mail: [email protected]). Singh Government Medical College For Women, Sonipat, Haryana, India

Ann Natl Acad Med Sci (India):2020;56:224–226

Abstract Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) has been declared as a pandemic by the World Health Organization (WHO). This new disease is a challenge for the managers of health care facilities and mortuaries. It has impacted the practice of whole medical community. Though there is literature available on route of transmission of virus and time span for which virus is active on surfaces but there is no data available on how long the virus lives in and is active on the surface of a dead body. Thus, the health care profes- Keywords sionals who handle cadavers and their specimens should use professional judgment to ►►dead bodies determine if a decedent had signs and symptoms compatible with COVID-19 during ►►mortuary life and if autopsy is mandatory. Ministry of Health and Family Welfare and Centre for ►►COVID-19 Disease Control & Prevention (CDC) have issued guidelines on dead body management ►►health care and collection of postmortem specimens which should be observed in mortuary area

professionals and laboratories to limit the spread of disease among health care workers.

Introduction or performing postmortem procedures. People may also become infected by touching a contaminated surface and Coronavirus disease 2019 (COVID-19) is an infectious dis- then touching their face.5-7 The asymptomatic carriers of ease caused by severe acute respiratory distress syndrome the virus tend not to get tested and contribute significantly coronavirus 2 (SARS-CoV-2), a member of the betacorona- to the spread of disease.8,9 The standard method of diagno- 1,2 virus family. It was first identified in December 2019 in sis is by real time reverse transcriptase polymerase chain Wuhan and since then had spread globally. World Health reaction from a nasopharyngeal (NP) swab. Recommended Organization (WHO) declared it a pandemic on March 11, measures to prevent infection include frequent hand wash- 2,3 2020. As it is caused by a novel coronavirus, the exact ing, maintain physical distance from others especially from pathophysiology of the disease, its course, and therapeutics those with symptoms, quarantine, covering coughs, and are not fully understood, as of now. As a result it has led to keeping unwashed hands away from face.10,11 Till date, there considerable anxiety and panic not only in general public but are no available vaccine nor specified antiviral treatment for 4 also among the health care workers. However, from a living COVID-19.5 This new disease is a challenge for the whole person, the virus spreads between people during close con- medical community including paramedics, and they are at tact (i.e., within approximately 6 feet), often via small drop- significant risk of getting infection if standard infection pre- lets produced by coughing, sneezing, and talking. This route vention and control measures are not taken. of infection is not a concern when handling human remains

DOI https://doi.org/ © 2020. National Academy of Medical Sciences (India). 10.1055/s-0040-1721555 This is an open access article published by Thieme under the terms of the Creative ISSN 0379-038X. Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/). Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India Handling of Cadavers in Mortuary Amidst COVID-19 Pandemic Gupta et al. 225

According to WHO, dead bodies are generally not infec- 8. Dead bodies should be stored in cold chambers main- tious except in cases of hemorrhagic fevers (Ebola, Marburg) tained at approximately 4°C. and cholera. Only the lungs of the patients with pandemic 9. Embalming of dead body should not be allowed to avoid influenza, if handled improperly during autopsy can be excessive manipulation of the body. infectious. WHO further adds that any body fluids leaking 10. Adults more than 60 years of age and immunosuppressed from orifices in the cadavers must be contained. There is no persons should not directly interact with the body. need to disinfect the body before transfer to the mortuary area.12 Precautions Taken during Autopsy Procedure The first incidence of COVID-19 being transmitted from a dead body to a medical professional in a Forensic Medicine Standard precautions, contact precautions, and airborne pre- unit occurred in Thailand on April 14, 2020.13 However, in cautions with eye protection (goggles or a face shield) should India, no such case has been reported till date. be followed during autopsy. These are consistent with the Although not much is known about how long the novel existing guidelines for safe work practices in the autopsy coronavirus can live in dead bodies, yet “anyone coming in setting.17,18 contact with a COVID-19 positive body alive or dead should be using personal protective equipment (PPE) to prevent Personal Care exposure” Health policy expert Summer Johnson McGee of 1. The number of forensic experts and support staff in the the University of New Haven told BuzzFeed News by e-mail. autopsy room should be limited and well trained in infec- Coroners are increasingly being asked to conduct investigation prevention control practices. tions into the cause of death for patients who had died and 2. Mortuary staff preparing the body (e.g., washing the body, were not tested. She further added that autopsies and the tidying hairs, trimming nails, or shaving) should wear subsequent investigations pose real risks for coroners to get appropriate PPE. infected by COVID-19.14 3. The team should use full complement of PPE (coveralls, The infectious disease specialist and assistant professor at head cover, shoe cover, N-95 masks, goggles, face shield). the University of Alberta, Dr. Schwartz said, “It would be pos- 4. Only one body cavity at a time should be dissected. sible that the virus could persist and remain infectious in or 5. Allow only one person to cut at a given time. on the body of someone who has died.”15 6. A logbook including names, dates, and activities of all workers participating in the postmortem and cleaning

Guidelines on Dead Body Management in the of the autopsy suite should be kept to assist in future Mortuary follow-up.

Government of India, Ministry of Health and Family Welfare Recommended Equipments to Be Used Are (MoHFW) Director General of Health Services (EMR Division) has issued guidelines on dead body management on March 15, 1. Aerosol generating procedures such as use of an oscillat- 2020 based on the current epidemiological knowledge about ing bone saw should be avoided for known or suspected COVID-19. According to the guidelines, all the staff identified COVID-19 cases. Consider using hand shears as an alter- to handle dead bodies in the mortuary should be trained in native cutting tool. If an oscillating saw is used, attach a the infection prevention control practices and observe fol- vacuum shroud to contain aerosols. lowing standard precautions.16,17 2. Round-ended scissors should be used. 3. PM40 or any other heavy duty blades with blunted points 1. Hand hygiene is the first and foremost preventive measure to be used to reduce prick injuries. to be followed before and after the interaction with the 4. Unfixed organs must be held firm on the table and dead body. sliced with a sponge—care should be taken to protect 2. Use of PPE (e.g., water-resistant apron, gloves, masks, and the hand. eyewear). 5. Needle should not be resheathed after fluid sampling— 3. Safe handling of sharps. needles and syringes should be placed in sharp bucket. 4. Used equipments should be autoclaved or decontaminated with disinfectant solutions in accordance with established Engineering Control Recommendations for Autopsy infection prevention control measures. 5. All soiled/used linen should be handled with standard 1. Perform autopsy in an adequately ventilated room, i.e., precautions, put in the bio-hazard bag and the outer sur- at least natural ventilation with at least 160 L/s/patient face of the bag disinfected with hypochlorite solution. air flow. 6. All medical waste must be disposed of in accordance with 2. Room should have a minimum of six air changes per biomedical waste management rules. hour (ACH) for existing structures and 12 ACH for new 7. All the surfaces of mortuary like floor, mortuary table, structures. door handles should be wiped with 1% sodium hypochlo- 3. Negative pressure to be maintained in the mortuary. rite solution, allow a contact time of 30 minutes, then 4. Room should have air exhausted directly outside or allow to dry. through a high efficiency particulate aerosol filter.

Annals of the National Academy of Medical Sciences (India) Vol. 56 No. 4/2020 ©2020. National Academy of Medical Sciences (India). 226 Handling of Cadavers in Mortuary Amidst COVID-19 Pandemic Gupta et al.

PPE Recommendations for Autopsies 2 World Health Organization. Available at: http://www.who. int/dg/speeches/detail/who-director-general-s-opening- 1. Double surgical gloves should be worn. remarks-at-the -media-briefing-on-covid-19. Accessed March 2. Fluid-resistant isolation gown. 11, 2020 3. Waterproof apron. 3 Hui DSI, I Azhar E, Madani TA, et al. The continuing 2019-nCoV 4. Goggles/face shield. epidemic threat of novel coronaviruses to global health—the latest 2019 novel coronavirus outbreak in Wuhan, China. Int 5. Disposable N-95 respirator. J Infect Dis 2020;91:264–266 6. Shoe covers. 4 Srinivasan R, Gupta P, Rekhi B, et al. Indian academy of cytol- 7. Surgical cap. ogists national guidelines for cytopathology laboratories for handling suspected and positive COVID-19 (SARS-COV-2) patient samples. J Cytol 2020;37(2):67–71 Recommended Biosafety and Infection 5 World Health Organization. Q & A on coronaviruses. Available at: Control Practices during Specimen Collection https://www.who.int/news-room/q-a-detail/coronavirus-disease-covid-19. Accessed November 18, 2020 Following are the CDC, Government of India guidelines regard- 6 Centers for Disease Control and Prevention. Coronavirus Disease ing collection and submission of postmortem specimen from 2019 (Covid-19). How does the virus spreads. Available at: cdc. diseased (persons with known or suspected COVID-19).18 gov/coronavirus/2019-ncov/faq.html. Accessed November 18, NP swab is the preferred choice for upper respiratory tract 2020 7 European Centre for Disease Prevention and Control. Q & A swab-based SARS-CoV-2 testing. Collection of NP swab speci- on COVID-19. Available at: ecdc.europa.eu/en/covid-19/ques- mens from a dead person will not induce coughing or sneezing, tions-answers. Accessed November 18, 2020 a negative pressure room is not required, however, standard 8 Bai Y, Yao L, Wei T, et al. Presumed asymptomatic carrier trans- precautions should be observed. Biosafety cabinet for han- mission of COVID-19. JAMA 2020;323(14):1406–1407 dling and examining smaller specimens should be used. 9 “China Reveals 1541 symptom free virus cases under pressure”. The following PPE should be worn at a minimum: Available at: www.bloomberg.com. Accessed March 31, 2020 10 World Health Organization. Advice for public. Available at: •• Wear nonsterile nitrile gloves. https://www.who.int/news-room/q-a-detail/coronavirus-dis- •• If there is risk of cut or puncture wounds, wear heavy duty ease-covid-19. Accessed November 18, 2020 11 Guidance for social distancing for everyone in the UK. gloves over the nitrile gloves. Available at: https://www.gov.uk/government/publications/ •• Wear long sleeved impermeable gown. covid-19-guidance-on-social-distancing-and-for-vulnerable- •• Used plastic face shield/goggles. people/guidance-on-social-distancing-for-everyone-in-the-

uk-and-protecting-older-people-and-vulnerable-adults [now withdrawn] Biomedical Waste Management and 12 World Health Organization. Infection prevention and con- Environmental Cleaning trol during healthcare when COVID-19 is suspected: interim guidance, January 25, 2020. Available at: http://www. •• After the procedure, discard the PPE in the appropriate who.int/publication-detail/infection-prevention-and-con- laundry or waste receptacle. Reusable PPE like face shield trol-during- health-care-when novel-coronavirus-(nCoV)-in- or googles, must be disinfected. Wash hands with soap fection-is-suspected-20200125. Accessed April 22, 2020 and water for 20 seconds. Avoid touching face.17,18 13 Won S, Viroj W. COVID-19 in forensic medicine unit personnel: •• The body of the deceased should be disinfected with 1% observation from Thailand. J Forensic Leg Med 2020;72:101964 14 Buzzfeed News. Available at: https://www.buzzfeednews. sodium hypochlorite and placed in a body bag, the exte- com/article/danvergano/coronavirus-spread-deadbody-coro- rior of which will again be decontaminated with 1% ner. Accessed April 13, 2020 sodium hypochlorite solution. 15 CBC News. Are dead bodies contagious? Your COVID-19 •• Autopsy table to be disinfected as per standard protocol. Questions Answered. Available at: http:/www. cbc.ca/news/ •• Keep ventilation system active while cleaning is conducted. covid-questioned-answered-bodies-1.5535139. Accessed April 17, 2020 •• Do not use water under pressure for cleaning as it may 16 COVID-19. Guidelines on dead body management. Available re-aerosolize infectious material. at: https:/ www.mohfw.gov.in/Pdf/1584423700568-COVID 19 •• Dispose off human tissues according to routine procedures. guidelines on dead body management. Accessed March 15, 2020 17 World Health Organization. Infection prevention and control Disinfect/Autoclave Instruments for the safe management of a dead body in the context of COVID-19. Interim Guidance. Available at: http:/apps.who.int/ The body thereafter can be handed over to the relatives. iris/handle/10665/331538. Accessed March 24, 2020 Conflict of Interest 18 Centre for Disease Control and Prevention (CDC). Collection and submission of postmortem specimens from deceased per- None declared. sons with known or suspected COVID-19. Interim Guidance. Available at: https:/ www.cdc.gov/coronavirus/2019-ncov/ hcp/guidance-postmortem-specimens.html. Accessed April References 22, 2020 1 Coronavirus disease 2019 (COVID-19)—symptoms and causes. Mayo Clinic 2020. Available at: Mayo Clinic.org/diseases-conditions/coronavirus/symptoms-causes/syc-20479963. Accessed November 18, 2020

THIEME Case Report 227

Pregnancy at the Cesarean Section Scar: Successful Management and Review of Current Literature

Pratibha Singh1 Sunil Raikar1 Garima Yadav1 Meenakshi Gothwal1 Navdeep Ghuman1

1Department of Obstetrics and Gynecology, All India Institute of Address for correspondence Pratibha Singh, MD, Department of Medical Sciences, Jodhpur, Rajasthan, India Obstetrics and Gynecology, All India Institute of Medical Sciences, Jodhpur 342005, Rajasthan, India (e-mail: [email protected]).

Ann Natl Acad Med Sci (India):2020;56:227–230

Abstract When implantation of the early embryo occurs at the scar of previous cesarean, it is called cesarean scar pregnancy. Though in uterus, it behaves like an ectopic pregnancy with risk of rupture and hemoperitoneum. A 37-year-old woman came with missed period and vague abdominal discomfort; she had a positive pregnancy test. She had previous two cesarean sections. The last cesarean section was 12 years ago and the patient was not using any contraception. Her ultrasonography (USG) was inconclusive; β human chorionic gonadotropin was 2,980 mIU/mL. Her repeat USG showed a hypoechoic area at the cesarean scar site, behind the reflection of bladder, sepa- rated from bladder by a thin layer of myometrium. She was counseled regarding the Keywords management options and prognosis. She was managed with two doses of injection. ►►cesarean scar Methotrexate on day 1 and day 4. β human chorionic gonadotropin was repeated until pregnancy it was close to normal. USG was also repeated. Cesarean scar pregnancy can be man- ►►scar site pregnancy aged by many ways; the one most suitable to the patient with least side effects should

►►ectopic pregnancy be adopted, after adequate counseling of the patient.

Introduction misdiagnosed4,5 and can be challenging to the obstetricians. This can lead to avoidable complications, for example, hemo- Location of pregnancy outside the uterine cavity is consid- peritoneum, shock, emergency hysterectomy, and rupture of ered as ectopic pregnancy and the fallopian tubes are consid- uterus in future pregnancy.5 ered as the commonest site for it. Cesarean scar pregnancy We report this case not only for its rarity, but also for occurs if the gestational sac is implanted in uterus at the site timely diagnosis, and successful treatment after discussing 1 of previous scar of cesarean section or hysterotomy. This all options of management with the patient. generally leads to invasion of this area by trophoblasts leading to further thinning and rupture of this area with conse- Case Report quent hemoperitoneum.2 Rarely cases of live births have also been reported.1 Previous uterine cesarean or hysterotomy A 37-year-old para 2 woman came with vague lower abdom- scar is the only risk factor for this type of pregnancy. The inal discomfort and missed period. She had previous two occurrence of cesarean scar pregnancy is likely to increase cesarean sections; the last was 12 years back. She was not due to better sonographic equipment and rising numbers using any contraception. She was a known diabetic for the of cesarean scars; presently, it is estimated to be 1:1,800 to past 5 years and was on oral hypoglycemic agents. She did 2,500 of all cesarean deliveries performed.3 a urine pregnancy test at home, which was positive. As she Though the resolution of sonography machine has did not want this pregnancy, she went for medical termi- improved considerably, diagnosis of cesarean scar pregnancy nation of pregnancy to a local practitioner and an abdom- is challenging, often being confused as failing intrauterine inal ultrasonography (USG) was done which failed to show pregnancy and inevitable abortion. It has been reported any gestational sac. So her β human chorionic gonadotropin that as many as 76% of cesarean scar pregnancy might be (HCG) was done, it was 2,980 mIU/mL.

DOI https://doi.org/ © 2020. National Academy of Medical Sciences (India). 10.1055/s-0040-1709225 This is an open access article published by Thieme under the terms of the Creative ISSN 0379-038X. Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/). Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India 228 Pregnancy at the Cesarean Section Scar Singh et al.

She came to our hospital with this history and reports of Table 1 Timeline of management with β human chorionic USG and β HCG. Her examination revealed stable vitals, soft gonadotropin and USG abdomen. Pelvic examination showed healthy cervix and No. Day β HCG (mIU/mL) Management done soft anteverted uterus without any cervical motion tender- ness. Her transvaginal USG revealed endometrial thickness 1 0 2,980 of 10 mm, a hypoechoic area located anteriorly above the 2 1 Methotrexate injection internal os, close to the bladder reflection (►Fig. 1). It had a (1 mg/kg body weight) fetal pole corresponding to 7 weeks of pregnancy. The myo- 3 3 3,250 β HCG showed a rise metrium over the sac was thinned out. Diagnosis of cesarean after 48 hours. scar pregnancy was made on suggestive USG picture. Patient 4 4 Second dose of metho- and her husband were informed about the case and the prob- trexate injection given lems associated with it. Management options were discussed 5 5 2,220 Falling trend of β HCG with them, as it was an unwanted pregnancy she opted for 6 7 day 960 Follow-up medical management with methotrexate. 7 2 weeks 440 TVS—tiny hypoechoic Patient was given methotrexate injection (1 mg/kg body crumpled sac seen weight) on day 1. Her β HCG was repeated after 48 hours 8 3 weeks – Follow-up which was 3,250 mIU/mL and her complete blood count was 9 4 weeks 67 TVS repeated—no sac also repeated which was within normal limits. She was given seen a second dose of methotrexate injection on day 4. Her repeat 10 5 weeks 5 Follow-up β HCG showed a declining trend and was 2,220 mIU/mL. She Abbreviations: HCG, human chorionic gonadotropin; TVS, transvaginal was followed with weekly β HCG, which was 5 mIU/mL after sonography. 5 weeks (►Table 1 and ►Fig. 2). She did not develop any problems with methotrexate injection like jaundice, mouth ►Fig. 1 shows transverse section showing gestational sac ulceration, gastritis, urinary problems, etc. in the myometrium close to bladder reflection anteriorly and Transvaginal sonography was repeated after 2 weeks and some calcification at the endometrial cavity. 4 weeks; which at 2 weeks showed a gestational sac was much smaller in size and crumpled, and at 4 weeks it was undetectable. Observation

The management and the follow-up of this patient are depicted in ►Table 1. Trends in beta HCG are depicted in ►Fig. 2.

Discussion

Cesarean scar pregnancy is a unique type of pregnancy, though present in uterus many like to consider it as ectopic pregnancy. A history of previous delivery by cesarean section is needed for the diagnosis of cesarean scar pregnancy. A history of previous uterine cesarean scar, missed period/ positive urine pregnancy test, and the typical USG picture is required for the diagnosis of cesarean section scar pregnancy. Transvaginal sonography gives a better resolution; and empty uterine cavity and empty endocervical canal, gestational sac at the lower uterine part near the bladder reflection, away from the uterine cavity with rim of myometrium over it gives a clue for diagnosis. Fetal pole and yolk sac may or may not be present depending on the duration of pregnancy. Close reflection of bladder peritoneum near the lower part of cervix tells about the location of previous scar of cesarean. A closed cervix and empty cervical canal helps in ruling out incomplete abortion and cervical ectopic pregnancy, an important differential diagnosis.5 3D and 4D USG images give accurate location of this type of pregnancy, where images can be reconstructed to see gestational sac away from the endo- metrium, at the bladder reflection and thin stretched myometrium over it. Adding color to it shows high vascularity, Fig. 1 Cesarean scar pregnancy. and better delineation of blood vessels can be seen.

Fig. 2 Trends of β human chorionic gonadotropin with methotrexate injection (arrow points to administration of methotrexate injection).

Treatment of cesarean scar pregnancy needs to be indi- Individualized treatment according to patient’s character- vidualized. If the gestational sac is empty, or the fetal pole istics and wishes taking care of contraindications and side or cardiac activity is not seen and the β HCG is stationary effects should be practiced to have the best results. Early pel- or suboptimally rising a possibility of failing pregnancy vic USG, preferably transvaginal is recommended for early and deserves careful follow-up by transvaginal sonography and diagnosis of this condition. It also stresses the need for effec- estimation of β HCG. However, some may still prefer to give tive contraceptive practices to avoid unwanted pregnancies. methotrexate injection in such condition. A rising HCG and/ or appearance of cardiac activity in such a situation should be treated with methotrexate, which can be given as single dose Conclusion or multiple doses. Both of them have been equally effective in Cesarean scar pregnancy is likely to rise in incidence due to treating ectopic pregnancy; however, multiple doses of meth- increasing numbers of cesarean sections. Timely diagnosis otrexate are associated with more side effects.6 Intralesional with typical USG characters need to be looked for early diag- methotrexate may be more effective if the size of sac is more nosis. There is no single best treatment for this condition. than 5 cm and presence of cardiac activity and if future fertil- Individualized management of patients taking care of her ity is desired.7 Alternatively uterine artery embolization and wishes, contraindications, and side effects can give satisfac- local Methotrexate7,8 may also be effective. There have been tory results. reports of treating cesarean scar pregnancy vaginally by suc- tion evacuation under USG guidance, but brisk bleeding is a Conflict of Interest risk which may require local balloon tamponed.8 If the patient None declared. wishes to continue pregnancy risk of hemorrhage, adherent placenta, uterine rupture necessitating hysterectomy and need for a repeat cesarean needs to be counseled to her by References 5 the treating physician. If the patient presents late after rup- 1 Timor-Tritsch IE, Monteagudo A, Santos R, Tsymbal T, Pineda ture, excision of the pregnancy or even hysterectomy may be G, Arslan AA. The diagnosis, treatment, and follow-up of needed. Intralesional methotrexate guided by USG has also cesarean scar pregnancy. Am J Obstet Gynecol 2012;207(1): been done9 with success. Methotrexate systemic as single or 44.e1–44.e13 multiple doses or intralesional is the commonly preferred 2 Gao L, Huang Z, Zhang X, Zhou N, Huang X, Wang X. Reproductive outcomes following cesarean scar pregnancy - a treatment.8 Intralesional methotrexate is a good choice if the case series and review of the literature. Eur J Obstet Gynecol pregnancy has cardiac activity and is 6 to 8 weeks in size. Reprod Biol 2016;200:102–107 Side effects of methotrexate are more with multiple dosing. If 3 Fu LP. Therapeutic approach for the cesarean scar pregnancy. the pregnancy grows toward the uterine cavity after implan- Medicine (Baltimore) 2018;97(18):e0476 tation, it is possible to have term pregnancy. Evidence-based 4 Wang YL, Weng SS, Huang WC, Su TH. Laparoscopic manage- management of cesarean scar remains unclear; hence, these ment of ectopic pregnancies in unusual locations. Taiwan J Obstet Gynecol 2014;53(4):466–470 patients need to be individualized for management.10,11 5 Timor-Tritsch IE, Monteagudo A. Unforeseen consequences In our patient, we had given two doses of methotrexate of the increasing rate of cesarean deliveries: early placenta injection as the β HCG was raised after the first injection. She accreta and cesarean scar pregnancy. A review. Am J Obstet did not develop any systemic side effects of methotrexate. Gynecol 2012;207(1):14–29

6 ACOG Practice Bulletin No. 191, Mar 2018. Available at: https:// 9 Yin XH, Yang SZ, Wang ZQ, Jia HY, Shi M. Injection of MTX for the www.acog.org/Clinical-Guidance-and-Publications/Practice- treatment of cesarean scar pregnancy: comparison between Bulletins/Committee-on-Practice-Bulletins-Gynecology/ different methods. Int J Clin Exp Med 2014;7(7):1867–1872 Tubal-Ectopic-Pregnancy. Accessed March 6, 2020 10 Gonzalez N, Tulandi T. Cesarean scar pregnancy: a systematic 7 Seow KM, Wang PH, Huang LW, Hwang JL. Transvaginal sono- review. J Minim Invasive Gynecol 2017;24(5):731–738 guided aspiration of gestational sac concurrent with a local 11 Jurkovic D, Hillaby K, Woelfer B, Lawrence A, Salim R, Elson methotrexate injection for the treatment of unruptured cesar- CJ. First-trimester diagnosis and management of pregnancies ean scar pregnancy. Arch Gynecol Obstet 2013;288(2):361–366 implanted into the lower uterine segment cesarean section 8 Wang DB, Chen YH, Zhang ZF, et al. Evaluation of the transvag- scar. Ultrasound Obstet Gynecol 2003;21(3):220–227 inal resection of low-segment cesarean scar ectopic pregnancies. Fertil Steril 2014;101(2):602–606

THIEME Case Report 231

Unilateral Dyshidrosiform Pemphigus Vulgaris

Manju Daroach1 Dipankar De1 Sanjeev Handa1 Rahul Mahajan1 Vikarn Vishwajeet2 Uma N. Saikia2

1Department of Dermatology, Venereology and Leprology, Address for correspondence Dipankar De, MD, Department of Postgraduate Institute of Medical Education and Research, Dermatology, Venereology and Leprology, Postgraduate Institute Chandigarh, India of Medical Education and Research, Sector 12, Chandigarh 160012, 2Department of Histopathology, Postgraduate Institute of India (e-mail: [email protected]). Medical Education and Research, Chandigarh, India

Ann Natl Acad Med Sci (India):2020;56:231–233

Abstract Pemphigus vulgaris is an autoimmune disease characterized by fluid-filled blisters over body and mucosal surfaces. Localized pemphigus is a rare presentation of the disease. There are few reports of localized pemphigus in literature presenting as esophageal involvement, recurrent paronychia, conjunctival mass, foot ulcers, discoloration of toes with hyperkeratotic skin lesions, verrucous lesions, and dyshidrosiform pemphigus vulgaris. We present a case of dyshidrosiform pemphigus involving a foot following trauma. Histopathology and direct immunofluorescence confirmed our diagnosis. Keywords In our patient, the disease started as localized dyshidrosiform pemphigus and later ►►pemphigus vulgaris became generalized. This unusual presentation led to a delay in diagnosis and proper ►►dyshidrosiform treatment in this patient. Physicians should be aware of such rare presentations to aid ►►unilateral in the timely diagnosis and management of such patients.

Pemphigus vulgaris is an autoimmune bullous disease clini- no lesion elsewhere in the body. Two months later, he devel-

cally characterized by flaccid cutaneous blisters and erosions oped oral erosions and few similar lesions on upper trunk with mucosal involvement. Unilateral or localized forms of and upper limbs. On examination, there were tense vesicles pemphigus have been reported in literature. Some rare pre- and yellowish brownish crust on the right sole and its lat- sentations of pemphigus vulgaris include isolated esophageal eral margin (►Fig. 1). Flaccid fluid-filled vesicles and ero- involvement, recurrent paronychia, conjunctival mass, foot sions were present at the scar site (►Fig. 2). Few scattered ulcers, discoloration of toes with hyperkeratotic skin lesions, lesions were seen on the chest, abdomen, upper back, and verrucous lesions, and dyshidrosiform pemphigus vulgaris. upper limbs. Differential diagnoses at the time of presenta- We present a case of unilateral dyshidrosiform pemphigus tion included localized dyshidrosiform pemphigus vulgaris, vulgaris following limb trauma. vesicular eczema, bullous tinea pedis, and bullous erythema A 35-year-old man presented with tense as well as flac- multiforme. cid vesicular lesions and crusting on right foot. A known Tzanck smear from lesions on sole, scar area, and oral case of pemphigus vulgaris for past 10 years, he had been mucosa showed acantholytic cells. Histopathology (►Fig. 3A) treated with dexamethasone pulse therapy and azathio- and direct immunofluorescence (►Fig. 3B) were suggestive prine, followed by rituximab. He was in remission for past of pemphigus vulgaris. With a diagnosis of dyshidrosiform 3 years before this episode. Four months back he had frac- pemphigus vulgaris followed by generalization, he was ture right femur for which he was operated and internal fix- treated with prednisolone 40 mg/day and subsequently with ation of fracture was done. Four weeks following the surgery, rituximab 1 g two doses 2 weeks apart and had improvement. he developed vesicular lesions on his right sole followed by Dyshidrosiform pemphigoid is a well-known variant of pustulation and crusting. He was being treated as infected localized pemphigoid presenting as vesiculobullous lesions eczema from another facility with oral antibiotics and pred- on palms and soles.1 Dyshidrosiform pemphigus, however, is nisolone with minimal relief. Subsequently, he developed rarely seen2 (►Table 1). Palmoplantar involvement in pemphi- flaccid vesicles on the scar of surgery for fracture. There was gus vulgaris is a poor prognostic indicator.3 The presentation

DOI https://doi.org/ © 2020. National Academy of Medical Sciences (India). 10.1055/s-0040-1713184 This is an open access article published by Thieme under the terms of the Creative ISSN 0379-038X. Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/). Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India 232 Unilateral Dyshidrosiform Pemphigus Vulgaris Daroach et al.

Fig. 1 Tense blisters and crusting on sole of right foot and lateral margin.

Fig. 2 Flaccid clear fluid filled blister on scar area on right thigh.

Fig. 3 (A) Histopathology (hematoxylin and eosin stain, 20X magnification) shows suprabasal cleft with row of tombstones and mild perivas- cular inflammatory infiltrate in dermis. (B) Direct immunofluorescence study highlights intraepidermal deposition of immune-reactant in fish net like pattern.

Table 1 Summary of previous reported cases of dyshidrosiform pemphigus Serial Study Number of patients Clinical description Proposed mechanism Treatment no. reported, age 1 Gharami et al, 20102 1, 36-year-old female, Vesicobullous eruption Irregular Prednisolone and known case of pemphi- with crusting on soles, self-medication cyclophosphamide gus vulgaris for 6 years few lesions on trunk Characteristic histopathology and direct immunofluorescence 2 Borradori and 1, 48-year-old male, Vesiculopustular and Keratinolytic enzymes Prednisolone Harms,19947 known case of pemphi- bullous eroded lesions induced inflamma- gus vulgaris for 7 years on left sole, diagnosed tory changes leading as bullous tinea pedis to modification and Treated with antifun- increased expression of gals, relapse of similar pemphigus antigen lesions in 10 days at same site Characteristic histopathology and direct immunofluorescence 3 Present case 1, 35-year-old male, Tense blisters and Local inflammatory Prednisolone and known case of pem- crusting on right foot, changes post trauma rituximab phigus vulgaris for with few lesions on and surgery 10 years trunk, upper limb and oral mucosa Characteristic histopathology and direct immunofluorescence

Annals of the National Academy of Medical Sciences (India) Vol. 56 No. 4/2020 ©2020. National Academy of Medical Sciences (India). Unilateral Dyshidrosiform Pemphigus Vulgaris Daroach et al. 233 in our patient was unusual as the disease relapsed as pom- This unusual presentation led to a delay in diagnosis and pholyx like lesions, initially confined to the limb that had proper treatment in this patient. This case is being presented sustained trauma. Exact pathogenesis of dyshidrosiform to highlight a rare morphologic variant of pemphigus. pemphigus is unknown. This presentation can be explained Conflict of Interest by the hypothesis proposed in dyshidrosiform pemphigoid. None declared. Local inflammatory process can uncover the masked antigen and trigger the disease at local site.4 Our patient had trauma in his right limb followed by inter- References nal fixation of fracture. This may have led to inflammation 1 Michelerio A, Croci GA, Vassallo C, Brazzelli V. Hemorrhagic and local edema that might have triggered an inflamma- vesiculobullous eruption on the palms and the soles as pre- tory response unmasking or modulating pemphigus antigen sentation of dyshidrosiform bullous pemphigoid. JAAD Case Rep 2017;4(1):61–63 similar to Koebner’s phenomenon. In a report of dyshidro- 2 Gharami RC, Kumar P, Mondal A, Ghosh K. Dyshidrosiform siform pemphigoid secondary to venous stasis, the patho- Pemphigus vulgaris: report of an unusual case. Dermatol genesis was attributed to local inflammation analogous to Online J 2010;16(7):10 koebnerisation.5 Dyshidrosiform pemphigoid can precede or 3 Vaishnani JB, Bosamiya SS. Pemphigus: active or inactive? occur concurrently with generalized form.6 Indian J Dermatol 2009;54(2):186–188 In our patient, the disease started as localized dyshi- 4 Levine N, Freilich A, Barland P. Localized pemphigoid simulat- ing dyshidrosiform dermatitis. Arch Dermatol 1979;115(3): drosiform pemphigus and later became generalized. Other 320–321 possibilities considered in our patient were infected dyshi- 5 Shi CR, Charrow A, Granter SR, Christakis A, Wei EX. Unilateral, drosiform eczema, bullous tinea pedis, and bullous erythema localized bullous pemphigoid in a patient with chronic venous multiforme. Dyshidrosiform eczema and bullous erythema stasis. JAAD Case Rep 2018;4(2):162–164 multiforme is usually bilateral and was excluded based on 6 Lupi F, Masini C, Ruffelli M, Puddu P, Cianchini G. Dyshidrosiform Tzanck smear positivity and histopathology/direct immu- palmoplantar pemphigoid in a young man: response to dap- sone. Acta Derm Venereol 2010;90(1):80–81 nofluorescence characteristic of pemphigus. Tinea pedis was 7 Borradori L, Harms M. Podopompholyx due to pemphigus vul- ruled out with the help of potassium hydroxide mount exam- garis and Trichophyton rubrum infection. Report of an unusual ination of blister fluid that was negative. case. Mycoses 1994;37(3-4):137–139

THIEME Images 234

Hemorrhagic Bullous Lesions in the Oral Cavity

Ajay Chauhan1 Ankur Guliani2

1Department of Internal Medicine, Civil Hospital, Baddi, Address for correspondence Ankur Guliani, MD, Department of Himachal Pradesh, India Dermatology, Venereology and Leprology, Civil Hospital, Baddi, Solan, 2Department of Dermatology, Venereology and Leprology, Himachal Pradesh 173205, India (e-mail: [email protected]). Civil Hospital, Baddi, Himachal Pradesh, India

Ann Natl Acad Med Sci (India):2020;56:234–234

A 55-year-old female presented with an asymptomatic, blood- filled blister inside the oral cavity for last 2 days. There was no history of trauma, oral/dental surgery, and intake of hot and crispy foods. On examination, a single, well-defined, nontender hemorrhagic bulla of size 2 cm in diameter was observed over the lateral surface of the tongue (►Fig. 1). Bulla ruptured spon- taneously and healed within 5 to 6 days without any scarring. Rest of the mucocutaneous examination was normal. Here, oral cavity and teeth were normal and healthy. She was a known case of hypertension, but not taking regular medication. Her blood pressure was 170/120 mm of Hg at the time of visit. Complete blood counts and hepatic and renal function tests were normal. Her prothrombin time (PT/international normalized ratio) and activated partial thromboplastin time (aPTT) were within normal limits. Her fasting blood sugar level was 118 mg/dL and HbA1C was 6.2%. On the basis of classical clinical morphology and investi- Fig. 1 Single, well-defined hemorrhagic bulla of size 2 cm in diameter

gations, we reached the diagnosis of angina bullosa hemor- over the left side of lateral surface of the tongue. rhagica (ABH). ABH is characterized by the sudden and spontaneous of ABH is mainly clinical and histopathology is not required. appearance of generally single, painless hemorrhagic blisters However, it is important to look for and treat the predispos- 1 on oral mucosa not attributable to blood dyscrasias. The ing factors associated and differentiate it from other severe diameters of lesion may range from 2 to 3 cm that commonly chronic disorders of the oral cavity to avoid unnecessary involves soft palate; however, other sites may be involved medications. including buccal mucosa, lips, tongue border, epiglottis, and esophagus.1,2 Clinically, the blisters start as dark red to pur- Conflict of Interest ple, painless or rarely painful blisters that usually rupture, None declared. releasing blood mixed fluid, and leaving an eroded surface that heals without any treatment within 7 to 10 days.2 References The etiology of ABH is uncertain. However, many predis- 1 Supekar BB, Sawatkar G, Wankhade VH. Angina bullosa hem- posing factors have been identified; systemic diseases such orrhagica. Indian Dermatol Online J 2019;10(1):89 as diabetes mellitus, hypertension and chronic renal failure, 2 Singh D, Misra N, Agrawal S, Misra P. Angina bullosa haemor- and local causes such as trauma, hot and spicy foods, den- rhagica. BMJ Case Rep 2013;2013:bcr2012008505 tal procedures, and steroid inhalers.3 Common differentials 3 Horie N, Kawano R, Inaba J, et al. Angina bullosa hemorrhag- of ABH include bullous lichen planus, bullous pemphigoid, ica of the soft palate: a clinical study of 16 cases. J Oral Sci 2008;50(1):33–36 thrombocytopenia, and epidermolysis bullosa. The diagnosis

DOI https://doi.org/ © 2020. National Academy of Medical Sciences (India). 10.1055/s-0040-1713011 This is an open access article published by Thieme under the terms of the Creative ISSN 0379-038X. Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/). Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India Published online: 2020-10-26

THIEME Commentary 235

Role of Religious Practices in the Spread and Mitigation of COVID-19

Simarpreet V. Sandhu1 Hardas S. Sandhu2

1Department of Oral and Maxillofacial Pathology, Genesis Institute Address for correspondence Simarpreet V. Sandhu, MDS, MAMS, of Dental Sciences and Research, Ferozepur, Punjab, India Department of Oral and Maxillofacial Pathology, Genesis Institute 2Dr. Hardas Singh Orthopaedic Hospital, Amritsar, Punjab, India of Dental Sciences and Research, Ferozepur 152001, Punjab, India (e-mail: [email protected]).

Ann Natl Acad Med Sci (India):2020;56:235–238

Abstract The World Health Organization (WHO) declared novel coronavirus disease 2019 (COVID-19) as a global pandemic on March 11, 2020 which engulfed the world like wild fire in less than 2 months. It has played havoc with the lives of people restricting their movement, confining them to their homes for months, devastating the economy, and causing psychological issues in some of them. In the unprecedented threat of the COVID-19 pandemic and its devastating impact on communities and nations across the globe, religious leaders and faith-based organizations may play a crucial role in saving lives and mitigating the spread of the disease. Religious leaders and faith-based organizations are primary source of support, comfort, guidance, direct health care and social service, for the communities they serve and people who have staunch belief in them. Most of the religious-minded people visit their places of worship frequently Keywords and often join the congregations on special occasions, making them vulnerable to any ► ► COVID-19 infectious disease prevailing at that time. Ensuring awareness and dispelling pseudo- ►►coronavirus infection scientific practices is a necessity for such communities in India to contain and control ►►religious practices the coronavirus infection, as it presents unique threat owing to the geographical vast- ►►faith leaders ness and the complexity of its cultural and religious diversity, beliefs, and practices ►►spread of disease coexisting with poor social indicators in this country. A study was conducted to under- ►►pandemic stand the role of religious practices in the spread and mitigation of COVID-19.

Introduction across the globe, it appears that the religious leaders and faith-based organizations may play a crucial role in saving The novel coronavirus disease 2019 (COVID-19) pandemic, lives and mitigating the spread of the disease.3 Religion offers also known as the coronavirus disease pandemic, is an ongo- solace to billions of people grappling with the pandemic for ing global threat of infection caused by severe acute respira- which the solutions offered by the science and governments 1 tory syndrome-coronavirus-2. (SARS-CoV-2). The outbreak have fallen short of their goal so far. The dread of coronavirus was first identified in Wuhan, China, in December 2019. The has driven individuals even more closer to religion and ritu- World Health Organization (WHO) declared the outbreak as a als across the globe. Public Health Emergency of International Concern on January Some of the religious places have acted as first respond- 30 and a pandemic on March 11, 2020. As of June 29, 2020, ers and counsellors, combatting stigma, providing required more than 10.1 million cases of COVID-19 have been reported emotional support, food assistance, praying for the world in more than 188 countries and territories, resulting in more health care professionals, and also the policymakers.4 They than 502,000 deaths. However, more than 5.14 million peo- are frequently in position to advocate for social and legal 2 ple have been found to be recovered. change. By sharing clear, evidence-based steps to prevent With the unprecedented threat of the COVID-19 pandemic COVID-19, religious-inspired institutions can promote helpful and its devastating impact on communities and nations

DOI https://doi.org/ © 2020. National Academy of Medical Sciences (India). 10.1055/s-0040-1716940 This is an open access article published by Thieme under the terms of the Creative ISSN 0379-038X. Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/). Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India 236 Role of Religious Practices in COVID-19 Sandhu, Sandhu

information, provide reassurance to people in their commu- medical journals, online forums, blogs and the cumulative nities, and promote health-promoting practices.5 Religious experiences gained from personal visits to various places of leaders are integrated into their communities through ser- worship in India and abroad. vice and compassionate networks and are a critical link in the safety net for vulnerable people within their faith com- Discussion munity and disease communities as well. But some practices raise public health concerns. In Religious leaders and faith-based organizations are among Myanmar, a prominent Buddhist monk announced that the most trusted sources of information on communi- a dose of one lime and three palm seeds would confer ties’ activities, customs and traditions. In the era of the immunity.4,6 In Iran, a few pilgrims were filmed licking Shiite COVID-19 outbreak, their followers and community mem- Muslim shrines to ward off infection.7 Some of the earliest bers of a particular faith may trust and follow guidance coronavirus outbreaks were traced to religious services or about COVID-19 coming from faith leaders much more than pilgrimages.4 The European Centre for Disease Prevention advisories and guidance released by government and health and Control (ECDC) website data showed that high num- authorities. Faith leaders also have a special responsibility to ber of cases of COVID-19 were from countries with a high counter and address misinformation, misleading teachings, Roman Catholic population where the majority attend the and rumors, which can spread rapidly and cause great dam- Sunday Mass.6 The cases could have risen due to the initial age to the community. The health care and social services of infected person administering sacraments of holy commu- faith-based organizations are often more accessible, espe- nion or by contaminated concentrated bread and wine itself cially in rural communities and among marginalized people served on Sunday Mass or also due to person-to-person con- in society. Religious leaders should ideally partner with sci- tact in the Church. In South Korea, the outbreak intensified entists, physicians from their faith as such scientist(s)–the- rapidly after the virus was spread at a secretive church in ologist(s) and congregants are more likely to win the trust of Daegu,5 and Israel’s virus hotspot is Bnei Brak, where some people from the same faith. ultraorthodox people defied the nationwide lockdown to Despite a handful of religious leaders and clerics resist- attend services and weddings.6,7 The initial epicenter of ing calls to cancel religious and social services and other Iran’s outbreak was the holy city Qom. Pilgrims reportedly gatherings, large gatherings are already banned or discour- contracted the virus there and spread it in their own coun- aged in many countries.8,10 Recently the coronavirus pan- tries before shrines were shut down.3,8A gathering of the demic has resulted in the cancellation of mass gatherings

Tablighi Jamaat Islamic missionary movement brought fol- in Lourdes6 and the closure by Saudi Arabia of pilgrims to lowers from 30 countries to Malaysia in late February, and Umrah.11 Catholic services were suspended last month in is believed to have led to thousands of infections. A gather- Italy, and in other countries also. Saudi Arabia closed the ing of the Islamic sect Tablighi Jamaat in Delhi at Markaz, holy mosques in Mecca and Medina in early March and has Nizamuddin, led to the spread of coronavirus in many places cancelled Hajj 2020, which was expected to draw more of India.6 In Pakistan, coronavirus cases quadrupled during than 2.5 million pilgrims.11 For the first time in modern the holy month of Ramadan after the government decided history, Christians around the world commemorated Jesus to conditionally allow congregational prayers in mosques8. In Crucifixion without the solemn church services or emo- the Northwest Indian State Punjab, a 70-year-old Sikh priest tional processions marking Good Friday. Easter, Passover, after returning from Italy attended several religious meetings and Ramadan, which occur within weeks of each other, and visited Hola Mahalla, a Sikh festival that attracts approx- also faced major disruptions in a world locked down by the imately 300,000 people every day infecting many of his close coronavirus pandemic.12 contacts and eventually succumbed to the disease.5 A new Most faith communities like various temples and churches wave of coronavirus cases was also witnessed after stranded in Uttar Pradesh to Golden Temple, a famous Sikh shrine in pilgrims at Hazur Sahib in Nanded Maharashtra came Punjab, Char Dham in Uttarakhand, and Islamic Centre of back to Punjab. India–Darul Uloom Farangi Mahalhave cancelled in-person Unlike many countries, India presents unique concerns events and have quickly established a variety of platforms owing to its geographical vastness and the complexity of its and models for online worship and devotee care. Religious cultural and religious diversity, beliefs, and practices coexist- leaders should remember that they are important coming with poor social indicators, such as lower life expectancy munity role models for reinforcing recommendations and and high child mortality.9 Ensuring awareness and dispelling showing how communities can still maintain connection by pseudoscientific practices is a necessity for India to confront conducting faith activities in virtual form. the coronavirus. In the lockdown, religious organizations can Accurate information can reduce fear and stigma. Religious play a vital role in transmitting accurate scientific informa- leaders can access guidance in formats and lay language that tion about the Coronavirus. their members can understand. WHO guidance has been rep- licated and shared on certain social platforms.13 A Facebook group of over 6,300 clergies representing various traditions Materials and Methods across the world shares resources on infection-control mea- The present study is based on information from various sures that could be implemented by temples, masjids and sources like television news, print and social media, scientific churches.

There are existing, active, and effective networks of reli- Members can be prevented from becoming infected by gious leaders and communities working in partnership with avoiding practices involving touching or kissing of religious global, regional, national, and local public health initiatives objects and symbols of reverence.15 Some religious leaders which constitute essential component of the robust multi- and faith communities have encouraged their members to sector response to COVID-19. accept new ways to reverence for these objects like bowing UNICEF (United Nations Children’s Fund) and part- before sacred statues or icons, instead of touching them, ner organizations have launched a global multi-religious receiving a blessing from at least 1 m away and avoid the Faith-in-Action Initiative—the Religions for Peace and Joint distribution of Holy Communion.16 It is advisable to use Learning Initiative–to respond to the COVID-19 crisis.14 The individual pre-packaged boxes/servings of religious or cere- initiative has engaged religious leaders and scholars from monial foods, rather than shared portions from communal Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, containers.18 Pakistan, and Sri Lanka to address key issues, including hon- The attendees should be encouraged to maintain oring international and national health authorities’ guidance healthy hygiene practices by providing handwashing facil- on religious mass gatherings, burials, rituals, and physical ities for members before and after the service; feet wash- distancing, promoting hygiene and sanitation and enhancing ing facilities for places where worshippers enter barefoot; social solidarity and non-discrimination across South Asia. or by placing alcohol-based hand-rub (having at least 70% WHO also acknowledges the special role of religious alcohol) at the entrance and in the worship space. There leaders, faith based organizations, and faith communities in should be a provision of visual displays of advice on phys- COVID-19 education, preparedness and response. ical distancing, hand hygiene, and respiratory etiquette. It is pertinent to ensure routine cleaning with disinfectant of worship spaces, pilgrimage sites, and other buildings Role of Broadcast Media and Social Media where people gather, to remove any virus from the sur- Religious leaders should also be aware of local and national faces. This routine should include cleaning and wiping the health authorities’ websites and other information channels surfaces immediately before and after all the gatherings. to access local guidance. It is pertinent to ensure that reli- Often-touched objects such as doorknobs, light switches, gious leaders have accurate and up-to-date scientific and and stair railings should be cleaned frequently with medical information to pass on to their congregations to slow disinfectant.18 the rate of disease spread. Sermons and messages should be Where gatherings are allowed by local health authorities, built on factual information provided by WHO and national religious leaders can perform ceremonies, such as weddings or local public health authorities both in government and and funerals, if they follow the guidelines for physical dis- non-government organizations; and in line with the doctrine tancing and by observing the limits set by national or local and practice of their respective faith traditions.15,16 public health authorities on the number of persons who can participate in such gatherings.18 When in-person gatherings cannot be held in accord with national or local public health Practical Considerations and guidelines, ceremonies may still be possible with essential Recommendations for Religious Leaders and members in attendance and a larger number of guests par- Faith-Based Communities in the Context of ticipating through distance via live streaming. Faith leaders COVID-19: Interim Guidance can help grieving families to ensure that their departed loved Religious institutions and faith-based organizations should ones receive respectful, appropriate funerals, and burial rites, protect their members by helping them maintain a safe even in the midst of the COVID-19 pandemic. distance between them (physical distancing). This is possible Religious leaders and faith communities should aim at by observing the following modalities: maintaining and strengthening relationships, fortifying the mental and spiritual health of followers and hence contrib- •• Discourage nonessential physical gatherings and orga- ute to resilience in the larger community. Practices, such as nize virtual gatherings through live-streaming, television, prayer, inspirational reading, and safe community service, radio, social media, etc.13 can build confidence and create a sense of calm and emo- •• If a gathering is planned, consider holding it outdoors.15 If tional support. this is not possible, ensure that the indoor venue has ade- Religious communities can identify ways that their mem- quate ventilation. bers can help others like checking on the elderly, people with •• Regulate the number and flow of people entering, attend- disabilities, and vulnerable neighbors by phone and offering ing, and departing from worship spaces to ensure safe dis- to deliver groceries.17 Religious leaders and faith communi- tancing at all times. ties can promote sharing of resources to provide for those •• Adaptation of religious practices to prevent touching whose livelihoods have been disrupted by the pandemic. between people attending faith services. In settings where movement restrictions are in place, Some greeting activities that need to be adopted within there is the potential for an increase in domestic violence, faith communities include replacing hugs and handshakes particularly against women, children, and other marginal- with a bow or using a greeting with folded hands while ized people.14 Religious leaders can actively speak out against maintaining physical distance.17,18 violence and can offer and arrange to provide support to the

victims. Religious leaders can provide faith communities 8 Bindu H. Faith over health? Why religious gatherings should be with appropriate prayers, theological and scriptural reflec- prohibited during coronavirus pandemic? Available at: https:// tions, and messages of hope, highlighting the opportunities www.grainmart.in/news/faith-over-health-why-religious- gatherings-should-be-prohibited-during-coronavirus- presented for reflection, and time with family members and pandemic/. Accessed May 25, 2020 others who can prove helpful. 9 Dharmshaktu NS. The lessons learned from current ongoing pandemic public health crisis of COVID 19 and its management in India from various different angles, perspectives and Conclusion way forward. Epidem Int 2020;5(1):1–4 10 Marrero T. Pastor of Tampa church that held two large Sunday services Religious rituals and practices involved at the common platform arrested, jailed. Available at: https://www.newsbreak.com/florida/ of worshiping like a temple, church, mosque, gurudwara, or any tampa/news/1537024610056/pastor-of-tampa-church-that-held- identified place of religious faith could play a role in the control two-large-sunday-services-arrested-jailed. Accessed June 15, 2020 of the spread of infection. During the ongoing COVID-19 pan- 11 Ebrahim SH, Memish ZA. Saudi Arabia’s drastic measures to demic, the religious places should be shut down and mass gath- curb the COVID-19 outbreak: temporary suspension of the erings cancelled or postponed on the basis of a context-specific Umrah pilgrimage. J Travel Med 2020;27(3):taaa029 12 McCloskey B, Zumla A, Ippolito G, et al; WHO Novel risk assessment. If a decision is made to open the place, risk mit- Coronavirus-19 Mass Gatherings Expert Group. Mass gather- igation measures should be put in place, consistent with WHO ing events and reducing further global spread of COVID-19: a guidance as defined by social distancing, mask wearing, and political and public health dilemma. Lancet 2020;395(10230) : soap hand washing/sanitization (SMS) practices for COVID-19, 1096–1099 and the rationale for the decision should be clearly explained 13 Amid Covid-19 lockdown, religious rituals, ceremonies take and communicated to the public. Religious leaders can be pow- digital avatar. Available at: https://www.hindustantimes.com/ india-news/amid-covid-19-lockdown-religious-rituals-ceremonies- erful resources for agencies like WHO and various government take-digital-avatar/story-U9awtF1OwYUTcKDwBfOxRL.html. and non-governmental organizations to transmit credible Accessed May 20, 2020 health information to their communities and bring messages 14 UNICEF. Launch of global multi-religious faith-in-action COVID-19 of hope for those struggling with anxiety, sadness, and despair. initiative, faith and positive change for children, families and communities. Available at: https://www.unicef.org/press-releases/ Conflict of Interest launch-global-multi-religious-faith-action-covid-19- None declared. initiative. Accessed August 31, 2020 15 Robinson K. How are major religions responding to the coronavirus? Available at: https://www.cfr.org/in-brief/ References how-are-major-religions-responding-coronavirus. Accessed May 17, 2020 1 Ashour HM, Elkhatib WF, Rahman MM, Elshabrawy HA. Insights 16 Berger M. Around the world, the devout are adapting their into the recent 2019 novel Coronavirus (SARS-CoV-2) in light of rituals to fit life under the coronavirus. Available at: https:// past human coronavirus outbreaks. Pathogens 2020;9(3):186 www.washingtonpost.com/world/2020/04/22/around-world- 2 WHO. Coronavirus disease (COVID-19) pandemic. Available at: devout-are-adapting-their-rituals-fit-life-under-coronavirus/. https://www.who.int/emergencies/diseases/novel-coronavirus- Accessed on May 15, 2020 2019. Accessed March 15, 2020 17 WHO. Practical considerations and recommendations for religious 3 Pennisi E. Does Religion influence epidemics? Available leaders and faith-based communities in the context of COVID-19 at:https://www.sciencemag.org/news/2011/08/does- Interim guidance. Available at: https://www.who.int/publica- religion-influence-epidemics. Accessed August 31, 2020 tions/i/item/practical-considerationsand-recommendations-for- 4 Kapila S. Will religion deliver us from or doom us to the pan- religious-leaders-and-faith-based-communities-in-the- demic? Available at: https://thewire.in/religion/religious- context-of-covid-19. Accessed May 29, 2020 congregations-coronavirus. Accessed June 16, 2020 18 Government of India Ministry of Health and Family Welfare. SOP 5 Quadri SA. COVID-19 and religious congregations: implications on preventive measures to contain spread of COVID-19 in religious for spread of novel pathogens. Int J Infect Dis 2020;96:219–221 places/places of worship. Available at: https://www.mohfw. 6 Escher AR Jr. An ounce of prevention: coronavirus (COVID-19) gov.in/pdf/2SoPstobefollowedinReligiousPlaces.pdf. Accessed and mass gatherings. Cureus 2020;12(3):e7345 June 15, 2020 7 Lawler, David, “God and COVID-19” (2020). Pandemic Response and Religion in the USA: Law and Public Policy. 61. Available at: https://scholarworks.wmich.edu/religion-pandemic-law/61. Accessed May 20, 2020

THIEME Commentary 239

BCG Vaccination and Immunity against COVID-19: A Fact or Fiction

Rajendra Prasad1 Rishabh Kacker1 Huda Shamim1 Nikhil Gupta2

1Department of Pulmonary Medicine, Era’s Lucknow Medical College & Hospital, Lucknow, Uttar Pradesh, India 2Department of General Medicine, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Ann Natl Acad Med Sci (India):2020;56:239–241

The first case of the novel Coronavirus disease, named doses of BCG vaccine are not recommended. BCG is prefer- COVID-19, was reported in Wuhan, China, on December 31, ably given at birth to provide protection in the early years 2019. The illness has variable manifestations, ranging from when infection can often lead to diseases such as miliary common cold to the more severe Middle East respiratory TB or tubercular meningitis. By the late 1940s, several stud- syndrome (MERS) and severe acute respiratory syndrome ies had appeared, providing evidence in favor of the utility (SARS). While the mortality rates of SARS and MERS was of BCG in protection against TB. In 1950s, major trials were estimated to be approximately 12% and 30%, respectively, set up by the Medical Research Council in the United King- the mortality rates in cases of COVID-19 is estimated to be dom and by the Public Health Service in the United States. much lower at around 4.03%.1 Nevertheless, the pandemic Soon it became evident that the procedure employed in the of COVID-19 is an issue that needs to be taken seriously. United Kingdom was highly efficacious against TB,4 whereas However, there are striking differences on how COVID-19 is that in the United States provided little or no protection.5 On behaving in different countries. For instance, in Italy, where the basis of these results, health agencies recommended even though social interactions were severely curtailed, the BCG as a routine for tuberculin-negative adolescents in the mortality is quite high as compared with Japan, where the United Kingdom, whereas BCG was not recommended for mortality is low despite not adopting restrictive social isola- routine use in the United States. The majority of the world

tion measurements. Even in India, which is the second most followed the lead of Europe and the WHO and introduced populous country in the world, the mortality rates are pretty routine BCG vaccination according to various schedules, low as compared with Italy and other European nations. whereas the United States and the Netherlands decided While these differences have been attributed to cultural against the use of BCG vaccination. norms as well as differences in medical care standards, an Due to the variability in results regarding the efficacy alternative explanation could be the national policy on of BCG vaccination in the previous trials conducted, a Bacillus Calmette–Guerin (BCG) vaccination. large-scale, community-based double blind randomized The BCG vaccine is a live attenuated strain derived from controlled trial was performed in Chingleput district of an isolate of Mycobacterium bovis. The vaccine has existed South India to evaluate the protective effect of BCG against for more than 80 years and is one of the most widely used of bacillary forms of pulmonary TB. The findings at 15 years all the current vaccines. Worldwide, more than 100 million showed that in this population with high-infection rates and children receive BCG each year.2 BCG vaccine was developed high-nonspecific sensitivity, BCG did not offer any protection over a period of 13 years, from 1908, by Albert Calmette and against adult forms of bacillary pulmonary TB.6 Despite the Camille Guerin. The original BCG vaccine strain was formerly backlash caused by the above study, BCG vaccine is still a part distributed by the Pasteur Institute of Paris and subcultured of the national immunization program in India. A plethora of in different countries using different culture conditions that data from studies provide strong evidence for BCG’s ability were not standardized.3 A limited rollout of vaccination was to protect against a wide range of infections other than TB, started in India in 1948 in an attempt to lower the tubercu- including nontuberculous mycobacteria (NTM), leprosy and losis (TB) burden in the country. By 1955–56, the mass cam- other bacteria (e.g., Shigella flexneri), viruses (e.g., vaccinia paign had covered all states of India. A single dose of BCG virus), protozoa (e.g., malaria), allergies, and eczema. vaccine is required to provide lifetime immunity. Booster Interestingly, the BCG’s immunomodulatory properties are

Address for correspondence Rajendra DOI https://doi.org/ © 2020. National Academy of Medical Sciences (India). Prasad, MD, DTCD, MBBS, A-28, Sector J, 10.1055/s-0040-1718860 This is an open access article published by Thieme under the terms of Aliganj, Lucknow 226024, Uttar Pradesh, ISSN 0379-038X. the Creative Commons Attribution-NonDerivative-NonCommercial-License, India (e-mail: [email protected]). permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/ licenses/by-nc-nd/4.0/). Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India 240 Commentary

routinely exploited in the treatment of bladder cancer and Also, health systems’ capacities, infrastructure, staffing, ICUs, melanoma.7 ventilators, and innate immunity of people are all confound- The possible link between BCG vaccination and its pro- ing factors which also need to be taken into account.12 And tective effects against COVID-19 came into limelight when although inconclusive, the prevailing weather and tempera- the global spread of COVID-19 was correlated with the ture also play a part in the spread and containment of an epi- data from the world BCG Atlas, and the study concluded demic, which is an idea that needs to be researched too, since that countries such as India, China and Japan with a pol- most tropical countries have had low caseloads. Whether icy of universal BCG vaccination have had a lower num- BCG will be effective remains unknown, as it is based on ber of cases than those in Spain, France, and Switzerland the findings from the ecological studies which are supposed which discontinued their universal vaccine policies. While to be a form of weak evidence.13 To settle this dispute, con- countries such as the United States, Italy, and Netherlands trolled trials are required. Currently, a randomized control have yet to adopt universal policies. This study also tries trial called BRACE trial is undergoing in Australia in which to explain the anomalous case of Iran, where the universal 4170 health care workers are being enrolled to evaluate the immunization program for BCG was only recently started in efficacy of BCG vaccination in providing immunity against 1984, unlike China and India, whose program goes back to COVID-19.13 Similarly, a trial in Netherlands aims to evalu- the late 1940s. Hence, most deaths in Iran comprise elderly ate the efficacy of BCG vaccination in reducing health care people who did not receive any immunization under the workers’ absenteeism in SARS-CoV-2.14 An upcoming trial by program.8 The possible explanation as to how BCG vacci- the Serum Institute of India is currently under consideration nation can provide immunity against the COVID-19 is that to test the efficacy of BCG in high-risk COVID-19 groups in this vaccine has been shown to produce positive “heterol- Maharashtra, India.15 The results of these trials will be able ogous” or nonspecific immune effects, leading to improved to prove or disprove about the protection of BCG vaccination response against other nonmycobacterial pathogens. In a against COVID-19. study conducted by Mathurin et al, the BCG-vaccinated Authors’ Contributions mice infected with the vaccinia virus were protected by R.P.: Chief author and editor; R.K.: Compilation of data; increased production of IFN-Ỳ by CD4+ cells.9 BCG vacci- H.S.: Data collection and editing; N.G.: Data collection and nation has also been shown to provide broad protection tabulation. against viral infections and sepsis,10 raising the possibility that the protective effect of the vaccine might not be Conflict of Interest

directly related to actions on COVID-19 but on associat- None declared. ed co-occurring infections or sepsis. In a recent study conducted by Miller et al, they found evidence that BCG vaccination seems to significantly reduce mortality asso- References

ciated with COVID-19. They also concluded that earlier a 1 Baud D, Qi X, Nielsen-Saines K, Musso D, Pomar L, Favre G. Real country established a BCG vaccination policy, the stron- estimates of mortality following COVID-19 infection. Lancet ger the reduction in their number of deaths per million Infect Dis 2020;20(7):773 inhabitants, which is consistent with the idea that pro- 2 Trunz BB, Fine P, Dye C. Effect of BCG vaccination on childhood tuber- tecting the elderly population might be crucial in reducing culous meningitis and miliary tuberculosis worldwide: a meta- analysis and assessment of cost-effectiveness. Lancet 2006; mortality.11 Even though the data might suggest the posi- 367(9517):1173–1180 tive role of BCG immunization against COVID-19, we must 3 Recommendations to assure the quality, safety and efficacy take into consideration that these are just mere observa- of BCG vaccines. WHO Technical Report Series No. 979, 2013. tions with limited evidence, and hence not a proven entity. Available at: https://www.who.int/biologicals/areas/vaccines/ Soon after the claim of BCG vaccination to confer immu- TRS_979_Annex_3.pdf. Accessed July 20, 2020 nity against COVID-19 was made, it was strongly opposed by 4 Hart PD, Sutherland I. BCG and vole bacillus vaccines in the prevention of tuberculosis in adolescence and early adult life. other researchers, who questioned the methodology and the BMJ 1977;2(6082):293–295 extent of COVID-19 spread globally at the time the study was 5 Comstock GW, Palmer CE. Long-term results of BCG vaccina- conducted and some of the presumptions were put forward. tion in the southern United States. Am Rev Respir Dis 1966; They pointed out the fact that there is a danger in citing that a 93(2):171–183 century-old vaccine may boost immunity in individuals and 6 Tuberculosis Research Centre. Fifteen year follow up of trial provide nonspecific protection against COVID-19 without of BCG vaccines in south India for tuberculosis prevention. Tuberculosis Research Centre (ICMR), Chennai. Indian J Med any clear evidence. It was also brought to attention that at Res 1999;110:56–69 the time when analysis was done, India had a fewer number 7 Report on BCG vaccine use for protection against mycobacteri- of cases as compared with the present scenario; hence, such al infections including tuberculosis, leprosy, and other nontu- speculations should not be made unless and until such obser- berculous mycobacteria (NTM) infections. The SAGE Working vations are proven by trials. Another major drawback of the Group on BCG Vaccines and WHO Secretariat. September 22, 2017. Available at: https://www.who.int/immunization/sage/ study was that the countries that were selected were arbi- meetings/2017/october/1_BCG_report_revised_version_ trary. Even Australia and Germany have a much lower mor- online.pdf. Accessed June 05, 2020 bidity and mortality rate and have no universal BCG immu- 8 New York Institute of technology. TB Vaccine Could Be a nization policy; hence, BCG solely cannot be the answer. Valuable Weapon in COVID-19 Fight. Available at: https://www.

forbes.com/sites/madhukarpai/2020/04/12/bcg-against- 13 Faust L, Huddart S, MacLean E, Svadzian A. Universal BCG coronavirus-less-hype-and-more-evidence-please/. Accessed Vaccination and Protection Against COVID-19: Critique of an May 05, 2020 Ecological Study. Available at: https://naturemicro biology- 9 Mathurin KS, Martens GW, Kornfeld H, Welsh RM. community.nature.com/users/36050-emily-maclean/posts/ CD4 T-cell-mediated heterologous immunity between myco- 64892-universal- bcgvaccination-and-protection-against-covid-1 bacteria and poxviruses. J Virol 2009;83(8):3528–3539 9-critique-of-an-ecological-study. Accessed April 15, 2020 10 Moorlag SJCFM, Arts RJW, van Crevel R, Netea MG. Non-specific 14 ClinicalTrials.gov. BCG Vaccination to Protect Healthcare Work- effects of BCG vaccine on viral infections. Clin Microbiol ers Against COVID-19 (BRACE). Available at: https://clinical- Infect 2019;25(12):1473–1478 trials.gov/ct2/show/NCT04327206. Accessed April 27, 2020 11 Miller A, Reandelar MJ, Fasciglione K, et al. Correlation between 15 ClinicalTrials.gov. Reducing Health Care Workers Absenteeism universal BCG vaccination policy and reduced morbidity and in Covid-19 Pandemic Through BCG Vaccine (BCG-CORONA). mortality for COVID-19: an epidemiological study. MedRxiv Available at: https://clinicaltrials.gov/ct2/show/NCT04328441. 2020 Doi: 10.1101/2020.03.24.20042937 Accessed May 05, 2020 12 Forbes. Available at: https://www.nyit.edu/box/features/tb_ vaccine_could_be_a_valuable_weapon_in_covid_19_fight. Accessed May 06, 2020

THIEME 242 Commentary

In response to “Telemedicine: An Era Yet to Flourish in India”

Neeraj Kumar1 Dinesh Sood1

1Department of Radiodiagnosis, Dr Rajendra Prasad Government Address for correspondence Neeraj Kumar, MD, Department of Medical College, Kangra, Himachal Pradesh, India Radiodiagnosis, Dr Rajendra Prasad Government Medical College, Kangra, Himachal Pradesh 176001, India (e-mail: [email protected]).

Ann Natl Acad Med Sci (India):2020;56:242–242

Telemedicine is the term used to describe any health care all over India. Patients get their reports within hours from delivery model whereby patient care is provided using infor- qualified radiologists even in remote centers. However, mation technology from far off places.1 Telemedicine can tele-ultrasound has a very limited role till date in India due overcome geographical and economical barriers in the health to the Pre-Conception and Pre-Natal Diagnostic Techniques sector. We would like to congratulate the author, Shilpa Act (PCPNDT Act), which requires radiologists and trained Sharma, for providing insight about telemedicine in India obstetricians to register their own ultrasound machines and in her article “Telemedicine: An Era Yet to Flourish in India” they have to be physically present.4 published in this esteemed journal.2 But the article has men- Conflict of Interest tioned an extremely limited role of teleradiology in reporting None declared. X-rays, although teleradiology has become the most flourish- ing branch of telemedicine nowadays. We would like to add that it is now routine to get online reporting of computed References tomography (CT) scans and magnetic resonance imaging 1 Serper M, Volk ML. Current and future applications of (MRI) scans in addition to X-rays. Teleradiology has been telemedicine to optimize the delivery of care in chronic liver able to overcome the scarcity of radiological services and disease. Clin Gastroenterol Hepatol 2018;16(2):157–161 3 personnel in rural areas and small towns. Even various state 2 Sharma S. Telemedicine: an era yet to flourish in India. Ann governments (Himachal Pradesh, Uttar Pradesh, Karnataka, Natl Acad Med Sci 2018;54(02):114–119 Maharashtra, Assam, Tamil Nadu, etc.) in India have estab- 3 Burute N, Jankharia B. Teleradiology: the Indian perspective. Indian J Radiol Imaging 2009;19(1):16–18 lished CT and MRI centers in district hospitals, civil hospitals, 4 Phutke G, Laux T, Jain P, Jain Y. Ultrasound in rural India: a fail- and even in medical colleges under public–private partner- ure of the best intentions. Indian J Med Ethics 2019;4(1):39–45 ship, which make use of telereporting by radiologists from

DOI https://doi.org/ © 2020. National Academy of Medical Sciences (India). 10.1055/s-0040-1721152 This is an open access article published by Thieme under the terms of the Creative ISSN 0379-038X. Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/) Thieme Medical and Scientific Publishers Pvt. Ltd., A-12, 2nd Floor, Sector 2, Noida-201301 UP, India Published online: 2020-12-31

THIEME Obituary 243

Prem Kumari Misra—The Doyenne of Pediatrics (1938–2020)

Sanjeev Misra1 Kuldeep Singh1

1All India Institute of Medical Sciences, Jodhpur, Rajasthan, India

Ann Natl Acad Med Sci (India):2020;56:243–244

Emeritus Prof. Prem Kumari Misra was born on September 22, year 2000, selected by the American Prem Kumari Misra 1938, in Farrukhabad of Uttar Pradesh (UP). Her father was a Biographic Institute, United States. renowned educationist and later became Director of Educa- She was an excellent orator and tion. She joined King George’s Medical College in 1955 for delivered several orations, including the Sir Shriram Memorial medical graduation (MBBS) and graduated in 1960, obtain- Oration of NAMS for 2004. Based on her contribution as a ing the second position in the institution. She went on to do teacher, researcher, and pediatrician, she was crowned with her DCH and MD in pediatrics from the same institution and many awards. Notable among them were the “Vigyan Ratna later joined the Department of Pediatrics as faculty in 1966. Award” of Council of Science and Technology, UP in 2008, “UP She took over the charge as Head of Pediatrics at KGMC in Ratna Award” by the National Association for the Intellectu- 1987. Because of her administrative and leadership qualities, als in 1995. Besides, she was also a recipient of the “Senior she was appointed Principal and Dean Faculty of Medicine Pediatrician Award” of UP State Branch of IAP in 2003, and in 1992. She superannuated as Principal in 1998 but due to “Life Time Achievement Award” by UP State Branch of NNF in her professional preeminence, she was given an extension 2004, and by UP State Branch of IAP in 2013. as Professor for two more years until 2000. Later she con- Dr. Misra has been a Fellow in the United States from tinued to guide students and became an Advisor for Neona- 1973 to 1974 and again in 1987 at the University of Chicago. tology and Pediatrics and Senior Consultant for DNB Pediat- She was also felicitated by various organizations, such as the rics in Vivekanand Polyclinic Institute of Medical Sciences in Indian Medical Association (IMA), Medical Council of India Lucknow. (MCI), and Lucknow University for her contribution as a cli-

She had a remarkable memory of remembering medical nician and by the Governor of UP on Teachers’ Day and King information through multiple editions of textbooks, and George’s Medical University as an outstanding teacher. her quotes used to stir discussions during grand rounds She has held many important posts in different commit- and seminars for the students to enrich their contemporary tees on training and care in the field of pediatrics and neona- knowledge. tology. She was a Regional Consultant for the Postgraduate Dr. Misra was a pioneer in starting and establishing the Diploma in Maternal and Child Health (PGDMCH) program specialty of neonatology in Uttar Pradesh. She established of Indira Gandhi National Open University (IGNOU). She has the first state-of-art neonatal intensive care unit (NICU) in been President of India CLEN, President of State Branch of IAP the state of UP, which immensely improved the newborn care NNF, and sponsor of Institute of Clinical Epidemiology. She and training of healthcare professionals in North India. Pro- has been a member of several journals’ editorial boards; a fessor Misra was the State Coordinator for National Neonatol- member of several committees; Executive Council member ogy Forum (NNF) and a Trainer in Neonatal Resuscitation in of UP King George’s Dental University, King George’s Medi- India. She has been a founder member of the executive board cal University, Lucknow; Chairperson of Expert Committee of NNF and President of UP State Branch of NNF. of Medical Research, Council of Science and Technology, UP; She has been a Fellow of the Indian Academy of Pediat- and Chairperson Ethics Committee and Stem Cell Research rics (IAP), National Academy of Medical Sciences of India Committee of King George’s Medical University, Lucknow. Dr. (NAMS), International College of Pediatrics (United States), Misra has been an Expert Member in Advisory Panel for Pedi- National Neonatology Forum (NNF), and Member of New atrics and Neonatology of NAMS for several years and Conve- York Academy of Sciences. She was a recipient of Dr. B.C. Roy ner of the State Chapter of NAMS. She has also been an Aca- National Award in the year 1990–1991 for the establishment demic Committee member and Academic Council of NAMS of the specialty of neonatology. She was the Woman of the from 2015 to 2018. Dr Misra has published over 170 papers

Address for correspondence DOI https://doi.org/ © 2020. National Academy of Medical Sciences (India). Sanjeev Misra, MS, MCh, FRCS, 10.1055/s-0040-1722358 This is an open access article published by Thieme under the terms of the Creative FAMS, FNASC, DSc(h.c.), All India ISSN 0379-038X. Commons Attribution-NonDerivative-NonCommercial-License, permitting copying Institute of Medical Sciences, Basni, and reproduction so long as the original work is given appropriate credit. Contents Jodhpur 342005, Rajasthan, India may not be used for commercial purposes, or adapted, remixed, transformed or (e-mail: [email protected]). built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/). Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India 244 Obituary

in national and international journals and also presented heavenly abode on February 18, 2020. Her passing signals almost a similar number of papers in various international the end of an era and the loss of an exemplary and iconic and national meetings. She has conducted several research human being. projects of national importance. Dr. Misra was also a devoted wife and mother. She was She was a brilliant academician, researcher, and teacher married to Dr. N. C. Misra, the renowned cancer surgeon. who trained and inspired generations of doctors. She exem- She is survived by her son Dr. Sanjeev Misra, Director, All plified the qualities of care, compassion, and clinical excel- India Institute of Medical Sciences, Jodhpur, Rajasthan, and lence, rare in these times. Admired by her young patients and daughter Dr. Sumita Misra, senior IAS officer of the Govern- their parents, she was an inspiration, especially for women ment of India. achievers, for her students and colleagues. She left for her

THIEME Obituary 245

Jitendra Nath Pande—The Doyen of Pulmonary Medicine (1941–2020)

K. K. Sharma1

1Former Professor and Head, Department of Pharmacology, University College of Medical Sciences and Guru Teg Bahadur Dr. Jitendra Nath Pande Hospital, Delhi, India

Ann Natl Acad Med Sci (India):2020;56:245–246

Dr. Jitendra Nath Pande, a renowned pulmonologist was Pro- and Annals of National Academy of Medical Sciences (India) fessor and Head of the Department of Medicine at the All (ANAMS) during 1996 to 2006. He received several awards India Institute of Medical Sciences (AIIMS), New Delhi. At the and accolades, some are Glaxo Oration of NAMS (1994–95), time of his untimely demise, he was working as Senior Con- Dr. K. L. Wig Oration of NAMS (1999–2000), Ranbaxy Science sultant (Medicine) at Sitaram Bhartia Institute of Science and Award (2000); and Om Prakash Bhasin Award of the Indian Research, New Delhi. Council of Medical Research (ICMR; 2010). He was Emeritus Born in the family of scholars in Shikohabad of Professor and Convener of NAMS Chapter of State of Delhi Uttar Pradesh on June 14, 1941, Dr. Pande was selected in and NCR, and he had delivered extension lectures at several AIIMS, New Delhi, in its third medical graduation (MBBS) medical institutions in the country. batch. He completed his medical graduation in December His colleagues and students remember him as an ency- 1962, with distinction and highest marks in several subjects. clopedia of medicine, pioneer of critical care in northern He passed MD (general medicine) in 1966 with a special India, and a dedicated teacher and doctor who always put interest in chest and respiratory diseases. patient care over and above any clinical work. Some of the Dr. Pande joined as faculty in the Department of Medicine fond remembrances are quoted below by those associated in his alma mater and in due course of time, rose to the post with him which bespeak the greatness of a medical teacher of Professor and subsequently became Head of the Depart- in him:

ment and superannuated from the same position in 2003. “As a professor, he used to reach the wards for the morn- After his retirement from AIIMS, New Delhi, Dr. Pande ing round at 7:30 a.m. to check on all the admitted patients joined the Sitaram Bhartia Institute of Science and Research even before his students,” remembers Dr. Anoop Misra, his and worked there as a senior consultant in the Department student, and now chairman of Fortis C-DOC Centre of Excel- of Respiratory Medicine. lence for Diabetes, Metabolic Diseases, and Endocrinology. Dr. Pande was actively involved in research in the field of “There were times when he would look at a patient and give respiratory physiology and chest diseases. He was a revered diagnosis in minutes.” Dr. Mishra further dwelled on his qual- teacher of medicine among his undergraduate and postgrad- ities as a physician par excellence. Even after becoming a doc- uate students. He published more than 170 papers in nation- tor in his own right, when Dr. Mishra remained unsure of the al and international journals of repute. Most publications diagnosis and had any trouble regarding the treatment to be were original research and got highlighted with worldwide followed for the concerned patient, he always consulted Dr. citations in journals and standard textbooks of respiratory Pande who will come out with the correct solution within an medicine. He contributed in investigation of cardiorespira- eye-blinking time. tory adaptation at high altitude, pathophysiology of chronic Dr. Ashok Kumar, who studied under Dr. Pande as an obstructive lung disease, pathophysiological changes in ane- MBBS and postgraduate student, currently Director of mia, and other hypoxic states. Rheumatology at Fortis Hospital at Vasant Kunj, New Delhi Dr. Pande was actively involved in the establishment of expressed, “it is a great loss to the entire medical fraternity. existing Cardiorespiratory Laboratories and designing and He helped set-up one of the first ICUs in the country. Many of establishing the first Intensive Care Units (ICUs) in Northern the current leading intensive care experts have been trained India at AIIMS, New Delhi. He served as the Editor of Indian under him. Sometimes, when we asked him a question, he Journal of Chest Diseases and Allied Sciences since the 1990s,

Address for correspondence DOI https://doi.org/ © 2020. National Academy of Medical Sciences (India). K.K. Sharma, A-5, Parivahan 10.1055/s-0040-1722359 This is an open access article published by Thieme under the terms of the Creative Apartments, Sector 5, Vasundhara, ISSN 0379-038X. Commons Attribution-NonDerivative-NonCommercial-License, permitting copying Ghaziabad 201012, Uttar Pradesh, India and reproduction so long as the original work is given appropriate credit. Contents (e-mail: [email protected]). may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/). Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India 246 Obituary

would reply with the exact page number and table we should even after joining this hospital. What has been remarkable refer to.” was that the most difficult cases would come to him.” Dr. G.C. Khilnani, former Head of the Department of Pul- Some important assignments fulfilled most diligently by monary Medicine at AIIMS, New Delhi, said “he was born to a Dr. Pande were physician and personal medical doctor to the family of teachers, he was my mentor and one of the greatest then Presidents of India, Dr. R. Venkataraman and Dr. Shan- teachers I know. At that time, many chose to go abroad and kar Dayal Sharma. Time to time, Dr. Pande was also involved practice medicine but he remained at AIIMS right from his in the medical treatment of many famous personalities from graduation to superannuation.” public life like Prime Minister of India, former Power Minister “Knowledge and humility can coexist and Dr. Pande was Rangarajan Kumaramangalam, and the Bollywood actor Raj an epitome of that. He was an excellent human being, and it Kapoor. Various assignments held by Dr. Pande were Director is a great loss to the medical fraternity. AIIMS family will miss of Clinical Epidemiology Unit; Chief of SRB Center of Clinical him the most because he joined AIIMS as an MBBS student Pharmacology; Department of Medicine, AIIMS, New Del- and retired as the Head of the Department of Medicine,” said hi. Dr. Pande was appointed as an expert member at ICMR Dr. Randeep Guleria, Director, AIIMS, New Delhi. He further Review Committee on 1985 Bhopal Gas Disaster. elaborated that “I have closely worked with him and knew The Supreme Court referred to Dr. Pande’s team’s study on him since my childhood as he was the student of my father.” “outdoor air pollution and emergency room visits at a hos- Mr. Abhishek Bhartia, Director, Sitaram Bhartia Institute pital in Delhi” in its 1997 to 1998 judgment, banning diesel of Science & Research, New Delhi, remembered Dr. Pande as buses in the capital. “a legendary physician who had taught many practicing doc- Dr Pande will be fondly remembered by everyone with tors at AIIMS, New Delhi, and continued to mentor physicians whom he has remained associated in life.

THIEME Obituary 247

Padmavati Sivaramakrishna Iyer—The Doyenne of Cardiology (1917–2020)

Shridhar Dwivedi1

1Department of Cardiology, National Heart Institute, New Delhi, India

Ann Natl Acad Med Sci (India):2020;56:247–248

Padmavati Sivaramakrishna Iyer Dr. Padmavati Sivaramakrishna Iyer was born in Rangoon, pulmonale, hypertension, and cor- Burma (Myanmar), on June 20, 1917 to a Barrister father with onary artery disease ever since she five siblings. She did her medical graduation (MBBS) from joined LHMC. She formed All India Heart Foundation (AIHF) Rangoon Medical College securing highest marks in the final in 1962 along with group of physicians and industrialist examination. Her family returned to India at the end of the Ashok Jain of Bennett, Coleman & Co. Ltd. Second World War. She went to England to pursue her higher On account of her sterling qualities of leadership and studies in Medicine, wherein she worked at National Heart academic brilliance, she was made Director-Principal of Hospital and National Chest Hospital, Queen Square, London. Maulana Azad Medical College (MAMC) in 1967. As the She did her Fellowship of Royal College of Physician (FRCP) Director-Principal, she was awarded the Padma Bhushan by from London in 1949. During this period, she developed Government of India in 1967. Later, she was awarded Fellow- interest in cardiology which remained her first love through- ship of the American College of Cardiology and the Fellow- out her life. Incidentally, her two sisters were renowned neu- ship of the National Academy of Medical Sciences (India). rologist and gynecologist, respectively. Soon after FRCP, she She developed Department of Cardiology in MAMC and laid went to Sweden for training in cardiology for 3 months. She down the foundations for Doctor of Medicine (DM) in Cardi- then went for scholarship at Johns Hopkins University at Bal- ology at Govind Ballabh Pant (GB Pant) Hospital where she timore in Maryland of the United States to study with noted subsequently became Director. Here, some of her illustrious cardiologist Dr. Helen Taussig in 1952. Later, she joined Har- students Prof. Khalilullah, Prof. Upendra Kaul, Prof. Sanjay vard Medical School to work under Dr. Paul Dudley White, Tyagi, and Dr. Vinod Sharma got their training and enjoyed the Father of Modern Cardiology. her blessings. Due to her passion and zeal for teaching and She returned to India in 1953 to commence her career as a research, she soon became a legend among her students. She lecturer in Medicine at Lady Hardinge Medical College (LHMC) was a born teacher who inspired generations of physicians to in Delhi. She started a regular cardiology clinic at LHMC. She choose cardiology as their specialty. Her unquenchable bril- was promoted to full Professorship and Headship at LHMC in liance and undaunted spirit to remain active always would due course of time. This was the time when All India Insti- live in the minds of innumerable students taught by her and tute of Medical Sciences was coming up in the national cap- the grateful patients. She rightly earned the reputation being ital in a big way, where Prof. Sujoy B. Roy was also trying to called as Helen Taussig of India (the famous lady cardiolo- set up Cardiac Catheterization laboratory in the Department gist who pioneered Blalock–Taussig shunts [BTS] procedure of Cardiology. Far south, at Christian Medical College in Vel- for the tetralogy of Fallot [TOF]). She retired as the Director lore, another noted lady Cardiologist Dr. K. I. Vytilingam too (Principal) of MAMC in 1978. was trying her best to develop state-of-the-art Cardiology Never to be tired, Dr. Padmavati established National Department. But such was the charisma and dedication of Heart Institute (NHI) as a clinical and research wing of the madam Dr. Padmavati that she made a deep impact in the All India Heart Foundation in 1981. This soon became one cardiology fraternity and organized first ever World Congress of the top cardiac centers of the country, now catering to all of Cardiology in Delhi and invited the top galaxies of cardiol- aspects of cardiology services, thanks to the dedicated efforts ogy from all over the world including Dr. Paul Dudley White. of its stalwarts and her students, Drs. O.P. Yadava and Vinod This Congress kept madam Padmavati on such a pedestal that Sharma. The writer of this column had the privilege of being she never looked back thereafter. She conducted epoch mak- examined by her in 1987 for PhD in cardiology at Banaras ing epidemiological studies on rheumatic heart disease, cor Hindu University. Her zeal for academics was such that, even

Address for correspondence Shridhar DOI https://doi.org/ © 2020. National Academy of Medical Sciences (India). Dwivedi, MD, PhD, FAMS, FRCP, FIACS, 10.1055/s-0040-1722360 This is an open access article published by Thieme under the terms of the Creative Department of Cardiology, National Heart ISSN 0379-038X. Commons Attribution-NonDerivative-NonCommercial-License, permitting copying Institute, New Delhi 110048, India and reproduction so long as the original work is given appropriate credit. Contents (e-mail: [email protected]). may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/). Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India 248 Obituary

at the age of over hundred years, she would be reading all and professional journey, spanning almost seven decades, cardiology journals and ticking topics for the weekly journal she left for her heavenly abode on August 29, 2020, valiant- club meetings for Diplomate of National Board (cardiology) ly fighting novel coronavirus disease 2019 (COVID-19). Thus students and enquiring about the outcomes of monthly came the end of an era. As rightly said, legends never die, they mortality meetings with senior colleagues. She also formed remain in the minds and hearts of those who adore them. Let a World Health Organization (WHO) Collaborative Centre me recapitulate few lines from Mundaka Upanishad which fit of Preventive Cardiology at NHI and always led from the so aptly for her life: front in matters of preventive cardiology and celebrated the World Heart Day punctually and regularly very year. She was awarded the India’s second highest civilian award the Padma Vibhushan in 1992 by the Government of India. On account of her monumental research work, she was Meaning: “just as a river’s flow is lost in an ocean, giving awarded fellowship of the European Society of Cardiology in up both their name and form; just so, the knower, freed from 2007 and Emeritus Professorship of Medicine and Cardiology name and form, the atma attains the unification with Divya by University of Delhi. Parmatma, the Virat Purusha, who is beyond the avyakta.” She was a voracious reader. In her younger days, she used Rest in peace God Mother of Cardiology. to swim briskly. After a very exciting and satisfying academic