Clinical Infectious Diseases SocietyNewsletter : October 2019

Website: www.cidsindia.orgVolume 6, Issue 9, October 2019Editor: Dr Ram Gopalakrishnan

Associate Editors: Dr Neha Gupta, Dr Ashwini Tayade, Dr Abi Manesh, Dr Raman Gaikwad, Dr Rajiv Karthik

Message from the CIDS Secretary

Dear CIDS members,

Thanks for the wonderful opportunity bestowed upon me to serve as the Secretary of CIDS. Our organisation hasmade small but significant strides since its inception. Our annual conference CIDSCON is one of the respected andanticipated academic events in the country.

Time has come for us to move forward as an organisation, be more inclusive and be more vibrant. We need to bemore visible in the field of antimicrobial resistance. I could personally get in touch with a few members of CIDS fortheir feedback on the same. Please feel free to voice your thoughts on taking our organisation to the next level. Icould be reached at 9841495288 or you could mail me at senthurnambi@gmail.com

Our monthly CIDS newsletter is an excellent compendium of advances in the field of Infectious Diseases. Significanthard work has been put in by the editorial team led by Dr Ram Gopalakrishnan to maintain its quality. In fact, thenewsletter is one of our trump cards and I wish that our newsletter reaches to a wider base of clinicians &microbiologists.

Looking forward for everyone’s support.

Sincerely,P Senthur NambiSecretary, CIDS

Editor’s note

Dear colleagues,

Our newsletter is now in its 7th year of continuous publication, and I am happy to assist in the transition of theeditorship of the newsletter to Dr Abi Manesh from Vellore, who will be taking over next year. I also welcome Dr RajivKarthik from Vellore to the editorial board. I am sure he and his colleagues will improve the newsletter further, andrequest all of you to send in ID news items, challenging cases, journal updates etc to further improve its quality. Iencourage all of you to circulate the newsletter to medical colleagues and juniors in various forums such as socialmedia, Whatsapp groups etc as a file or by sharing the link.

The society website has been updated with some of the talks at CIDSCON 2019 as an educational initiative, requestall to visit and encourage juniors and PGs to do so. All prior newsletter issues are archived there and can beaccessed free of charge by all.

I encourage all of you to utilize any senior member of CIDS as a visiting professor and reproduce below the policyfrom our website.

CIDS Visiting Professor program:

Aims and objectives

The purpose of the program is to expose students, postgraduates and faculty of a medical college without an IDdepartment, or physicians in a city with no or few ID physicians, to an eminent Infectious Disease physician for aday. This exposure will hopefully translate into better clinical practice of ID locally, stimulate interest in thesubspecialty and society, and in the long run, result in growth of the speciality and establishment of ID departmentslocally.

Methodology

Any medical college or city fulfilling the criteria above, could approach either CIDS or the visiting professor directly,and arrange a mutually convenient date and program.Any current or former CIDS executive committee member would qualify as Visiting Professor.To maximize academic time and minimize travel time and lodging expenses, single day morning to eveningprograms are preferred. A day long program would typically include

2-3 didactic lecturescity wide ID case conferenceward roundsclinic bedside teaching on patients with interesting and challenging ID problemsassistance with infection control issues

Funding

CIDS will pay for travel of the visiting professor, while the hosting organization will take care of local logistics andhospitality.

The EC of CIDS is to be informed of date, approximate travel cost and tentative program by email beforehand. Aftera brief feedback mail by the visiting professor after the program is given to the EC and expenses and receipts turnedin, reimbursement of expenses will be done.

Photoquiz

A 22 -year old gentleman with no other co-morbidities, presented with subacute onset progressively increasing painin back of upper part of neck since 20 days. Pain aggravated on walking and MRI spine showed- right C2-3 facetallesion, suggestive of Pott’s spine (Figure 1).

Figure 1: C2-C4 endplate irregularity with partial collapse of C3 vertebra, diffuse marrow edema of C2,3 and C4.There is mild pre and bilateral para-vertebral soft tissue thickening extending into neural foramen. Figure 2:Histopathology is suggestive of “giant” cells

He was initiated on weight–based anti-tubercular therapy (ATT). Since there was no improvement with trial of ATT,C3-4 laminectomy, drainage of right C3-4 facetal lesion was performed. Histopathology of the lesion revealednumerous giant cells (figure 2). AFB stain and MTB/RIF X Pert was negative in the intra-operative specimen.

What is your diagnosis?

ID NEWS

Chandipura Virus

Contributed by Dr Sowmya Sridharan

A suspected case of Chandipura virus was reported from village Siholadi, Kheda, Gujarat. A 6 year old malepresented with fever, foul smelling vomiting and foul smelling stools and convulsions. Serum sample was collectedand sent to NIV Pune and found positive for CHPV by PCR. Chandipura Virus (CHPV), a member of Rhabdoviridaewas first identified in 1965 after isolation from the blood of two patients from Chandipura villagein Maharashtra state, India. Chandipura vesiculovirus has been isolated from sandflies in India and West Africa .

Chandipura Virus, an enveloped RNA virus mostly affects children and is characterized by influenza-like illness andneurologic dysfunction. Sandfly bites infested cracks in walls or parts of homes made of sand or mud areepidemiologically linked to the disease. Neuropathogenesis of CHPV include disruption of the blood–brain barrierand release of reactive oxygen species (ROS) which stimulates neuronal death. Immunofluorescent antibodytechnique was successfully employed to detect the presence of CHPV in brain tissues during the 2003 outbreak inAndhra Pradesh. A reverse transcriptase PCR (RT-PCR) and real time RT-PCR have been standardized for routinediagnosis.

References

1. Chandipura Viral Encephalits - A Brief Review

ID NEWS

Crimean-Congo hemorrhagic fever (Rajasthan/Gujarat)

Contributed by Dr Ashwini Tayade

Two patients admitted in AIIMS Jodhpur, Rajasthan died of Crimean-Congo Haemorrhagic Fever (CCHF) in thisSeptember. The National Institute of Virology (NIV) had informed the state regarding seropositivity of CCHF amonglivestock. The NIV had conducted the serosurvey to analyze the risk of spreading of the disease. The first case ofCCHF in the country was recorded in Gujarat in 2011 and since then, several persons have died due to it. People whoare associated with animal husbandry and slaughter have higher chances of contracting the disease, which spreadsdue to tick-borne virus (Nairovirus) of the Bunyaviridae family. One of the largest studies undertaken by the statehealth department, ICMR-NIV , has pointed out for the first time, human population in 11 out of 33 district wereimmediately vulnerable to CCHF

Reference: BMC Infect Dis. 2019 Feb 1;19(1):104

ID NEWS

Japanese Encephalitis and other (Bihar)

Contributed by Dr Ashwini Tayade

30 cases were reported in July 2019, 18 in August 2019, while at least 12 cases have been reported in September2019. In all, 647 cases have been reported from 2019, out of which 161 children died.

AES has continued to be attributed to a variety of etiologies, including Reye syndrome-like disease, possibleenterovirus infection from polluted water, heatstroke, lychee fruit consumption, and scrub typhus (Orientiatsutsugamushi). A recent publication (reference below) states that dengue virus is one of the 3 most commonagents identified in AES, but existing surveillance for AES does not include routine testing for dengue. Etiologicalagents in many patients still remain undiagnosed. Until the etiology (or etiologies) of these AES cases is determined,effective and efficient prevention of these cases will not be possible.

Reference: Int J Infect Dis. 2019 Jul;84S:S19-S24

ID NEWS

US-FDA approval of pretomanid for treatment of drug resistant tuberculosis

Contributed by Dr Raman Gaikwad

Pretomanid was approved by US-FDA in August 2019 under a fast-track pathway for treatment of MDR-TB. Thisapproval was based on the preliminary results of a phase 3 study in South Africa (Nix-TB).

Nix-TB is a single arm study to assess the efficacy and safety of a 6 month all-oral BPaL (bedaquiline, linezolid,pretomanid) regimen. 109 patients with XDR-TB or non-responsive/treatment-intolerant MDR-TB were recruited andprimary efficacy endpoint data available for 81 patients at time of FDA approval. 90% of patients achieved relapse-free cure status 6 months after treatment end. The median time to culture negative status was less than 6 weeks.Preliminary 24 month data also indicates long term cure.

Regimen adverse effects were mostly associated with linezolid (peripheral neuropathy & myelosuppression) andcould be managed with dose modifications and drug withdrawal (83 patients). HIV positive patients (50%) hadsimilar outcomes, though patients with CD4 count < 50 cells /ul were excluded. In summary, the BPaL regimenrepresents a major advance towards a shorter and highly efficacious MDR-TB regimen.

Reference: US-FDA Slides

ID NEWS

Patients with MDR TB in India have limited access to bedaquiline

Contributed by Dr Raman Gaikwad

3 years after its introduction, most patients with MDR-TB in India are unable to access a key drug - bedaquiline.Bedaquiline significantly improves outcomes of drug resistant tuberculosis. The current drug supply in India wasdependent upon the now-ceased Bedaquiline Donation Program - a collaboration between USAID and J&J. Furtherdoses will have to be purchased at $900 per six month course, however no purchase agreement has yet beenreached. No indigenous manufacturing licence has yet been issued to ensure local supply. The drug remainsunavailable in the private sector. This state of affairs has drawn criticism from TB activists across India.

Reference: Caravan Magazine

JOURNAL REVIEW

Month long Antimicrobial Therapy for Infected Orthopedic Implants Enough?

J Antimicrob Chemother. 2019 Aug 1;74(8):2394-2399 Contributed by Dr Venkat Ramesh

Shorter therapies are becoming the norm in infectious diseases. We have useful data supporting non-inferior, shorterantimicrobial regimens in case of visceral leishmaniasis, cryptococcal meningitis, gram-negative bacteremia, nativejoint septic arthritis (reviewed in the CIDS newsletter in June 2019) and shorter primaquine therapy for vivax malaria.The duration of treatment in patients with infected orthopedic implants is unknown. The general consensus andtraditional teaching are a minimum of 6 weeks.

This is a single-center, randomized, prospective trial comparing 4-weeks vs. 6-weeks of pathogen-directedantimicrobial therapy for infected orthopedic implants. 123 eligible patients (median age, 64; 31%immunocompromised; 10% bacteremic) were randomized. The most common pathogen was Staphylococcusaureus. The most common types of infections treated included orthopedic plate infection (n=44), two-stageexchange procedure for prosthetic joint infection (38), and infected nail implants (11). 98% were curedmicrobiologically and 94% clinically after a median follow-up period of 2.2 years. No significant between-groupdifference in outcomes — including clinical and microbiological cure in either the per protocol or intent-to-treatgroups. This trial strongly supports the sufficiency of a 4-week antibiotic regimen in patients with infectedorthopedic implants following adequate source control with limitations of a small sample size.

JOURNAL REVIEW

Maribavir for Preemptive treatment of Cytomegalovirus reactivation in transplantrecipients

N Engl J Med. 2019 Sep 19;381(12):1136-1147 Contributed by Dr Rajiv Kartik

CMV is a common infection among post transplant patients and currently used anti-CMV agents are limited by theirtoxic effects. Maribavir, a novel antiviral, has a favorable safety profile with a unique mechanism of action potentiallyuseful against resistant strains. This open labeled, dose blinded study evaluated the use of maribavir at 3 doses(400mg, 800mg and 1200mg twice daily) in adult transplant recipients with evidence of CMV reactivation (1000 to100,000 DNA copies /ml) compared with standard dose of valgancyclovir. The primary efficacy end point was thepercentage of patients with a response to treatment, defined as confirmed undetectable CMV DNA in plasma, within3 weeks and 6 weeks after the start of treatment.

Of the 117 patients who received maribavir, 72 (62%; 95% CI 52 to 70) had a response to treatment within 3 weeks,as compared with 22 of the 39 patients (56%; 95% CI, 40 to 72) who received valganciclovir (risk ratio, 1.12; 95% CI,0.84 to 1.49); the percentages of patients with a response were similar among the different maribavir dose groups.The percentage of patients who had a response within 6 weeks was 79% (95% CI, 70 to 86) in the maribavir groupsand 67% (95% CI, 50 to 81) in the valganciclovir group, and the risk ratio based on the estimates of the treatmenteffect was 1.20 (95% CI, 0.95 to 1.51) .

Surprisingly the incidence of serious adverse events that occurred or worsened during treatment was higher in themaribavir group than in the valganciclovir group (52 of 119 patients (44%) vs. 13 of 40 (32%). A greater percentageof patients in the maribavir group discontinued the trial medication because of an adverse event [(27 of 119 (23%)vs. 5 of 40 (12%)] - primarily due to gastrointestinal adverse events.

Within the limitations of a phase 2 study it appears that maribavir at a dose of at least 400 mg twice daily hadefficacy similar to that of valganciclovir for clearing CMV viremia among transplant recipients though a there was asurprisingly higher incidence of gastrointestinal adverse events. Further studies are needed before maribavir can berecommended for preemptive CMV treatment.

JOURNAL REVIEW

Increasing evidence for 2 drug ART regime for maintenance of virologicalsuppression

Lancet HIV. 2019 Sep;6(9):e576-e587 Contributed by Dr Rajiv Kartik

There is growing evidence for the use of 2 drug ART regimes especially for the sustained maintenance of virologicalsuppression. The SWORD 1 and SWORD 2 studies are identically designed, randomised, open-label phase 3 studiesat 65 centres in 13 countries and 60 centres in 11 countries, respectively. In this study adults (>18 years) who wereon a standard three or four drug ART regime and were virologically suppressed ( VL < 50 HIV-1 RNA copies/ml) for atleast 6 months were randomly assigned (1:1) to 50 mg dolutegravir plus 25 mg rilpivirine orally once daily (early-switch group) or to continue their standard regimen for 52 weeks before switching to the dolutegravir plus rilpivirinecombination ( late-switch group). The primary efficacy end point was the proportion of participants with Viral load <50 copies/ml at week 100.

513 participants were randomly assigned to dolutegravir plus rilpivirine (early-switch group) and 511 to continuetheir standard ART regimen, 477 of whom then switched to dolutegravir plus rilpivirine at week 52 (late switchgroup). At week 100, 456 (89% ,95% CI 86–92) of 513 participants in the early-switch group and 444 (93% , 95% CI91–95) of 477 in the late-switch group had < 50 HIV-1 RNA copies per mL. Drug-related adverse events were mildand did not need regime modification and occurred in 103 (20%) participants in the early-switch group and 58 (12%)in the late-switch group.

It appears that the combination of dolutegravir plus rilpivirine results in the sustained virological suppression of HIV-1 , and was associated with a low frequency of virological failure, with a favourable safety profile. This supports itsuse as a NRTI and PI sparing alternative to three-drug regimens that reduces overall exposure to ART.

JOURNAL REVIEW

Endemic artemisinin resistance with novel pfKelch13 mutation confirmed in WestBengal

Clin Infect Dis. 2019 Sep 13;69(7):1144-1152 Contributed by Dr Raman Gaikwad

This study reports failure of artemesin combination therapy in 4 districts in West Bengal in 2014-2016. Artesunate-sulfadoxine-pyrimethamine (ASSP) therapy failed in 16% of these 226 patients (7.9% early failure, 7.9% late failure).12% patients had a parasite clearance half-life (PCLH) of more than 5 hours. 18% patients had a K13 propellerdomain (K13PD) (pfKelch13) polymorphism. A novel pfkelch13 G625R mutation was found in most of these patientsand was associated with a high PCLH. Furthermore, 50% of all studied isolates were resistant to sulfadoxine andpyrimethamine due to mutations in the pfdhfr and pfdhfs genes. All treatment failures were cured by artemether-lumefantrine ACT.

This study represents confirmation of endemic artemisinin resistance and high resistance to sulfadoxine-pyrimethamine in West Bengal. Notably the G625R mutation is different from the dominant resistant C580Y lineagein Greater Mekong Region and likely emerged indigenously. For clinicians treating malaria, artemisinin resistanceshould be considered in early / late treatment failures and use of ASSP should be avoided, at least in West Bengal.

PS: also refer to the subsequent exchange between WHO Global Malaria Program officials here and the studyauthors here - on whether G625R represents a true resistance mutation.

Conference Watch

ID Week, Oct 2-7, 2019, Washington DC, USAwww.idsociety.org

ECCMID, April 18-21, 2020, Paris, Francewww.eccmid.org

MYCOCON 2020 Chennai, July 17-19 [www.fisftrust.org ](http://www.fisftrust.org]

Are you an MD/DNB (Internal Med) interested in an ID career?

DM (Infectious Diseases)Three year programCMC, Vellore and AIIMS, New Delhi

FNB (National Board of Examinations):Two year fellowshipApollo Hospitals Chennai, Hinduja Hospital Mumbai, Apollo Hospitals Hyderabad, Sterling HospitalAhmedabad

Tamil Nadu Dr. MGR Medical University:Two year fellowshipGlobal Hospitals Chennai and CMC, Vellore

Answer to the photoquiz

Histological features were consistent with giant cell tumor, including sheets of round to oval, polygonal or elongatedmononuclear cells, which are interspersed with uniformly distributed, large osteoclast giant cells.

Giant cell tumor of bone is relatively rare, benign, but locally aggressive osteolytic skeletal neoplasm of young adults(20-40 years of age) with slight slight female preponderance. While most bone tumors occur in the flared area nearthe ends of the body's long bones (metaphysis), giant cell tumors most commonly affects the epiphyses of longbones. Less commonly involved sites include the vertebral bodies, pelvis, sacrum and craniofacial bones, and thesmall bones of hand and feet. Most cases are solitary lesion.

Tuberculosis is the most common infectious etiology affecting the cervical spine but it’s important for clinicians tokeep in mind the non-infectious causes. Biopsy, cultures and molecular studies should be obtained in all cases ofvertebral OM. Differentiating features between TB spine and Giant cell tumour are elaborated in Table 1.

TB Spine Giant cell tumor of spine

Constitutionalsymptoms

Pain, Fever, Weight Loss (insidious onset) may bepresent

Absence of fever, weight loss

ESR &Globulins

Increased Normal

MTB/RIF XPert

Positive in 40-50% Negative

ZN stain AFB seen (+/-) AFB not seen

ImagingDiscitis (disc involvement) with anterior epidural,paravertebral collection and necrosis

Intra-osseous lesions with surrounding softtissue involvement without liquefaction

Although giant cell tumor are not cancerous, they are aggressive and can destroy the surrounding bone. Treatmentfor a almost always involves surgery to remove the tumor and prevent damage to the bone near the affected joint. Ifsurgery is not possible then treatment with donesumab is an alternative. Nonsurgical treatment includes radiationand tumour embolization.

Final diagnosis: Giant cell tumour of the cervical spine

Case provided by; Dr. Ravi Bhushan (ID Fellow), Dr. Sudhir Dubey (Neurosurgery), Dr. Rajiv Gupta (Radiology), Dr. NehaGupta ( Infectious Diseases)