Clinical Infectious Diseases SocietyNewsletter : April 2019

Website: www.cidsindia.org Volume 6, Issue 4, April 2019

Editor: Dr Ram Gopalakrishnan Associate Editors: Dr Neha Gupta, Dr Ashwini Tayade, Dr Abi Manesh

Editor's Note

Hope all of you have registered for CIDSCON 2019 in Kochi Aug 23-25. The usual academic treat awaits us at India'spremier ID conference! The current society office bearers (President, Secretary, Treasurer) will be continuing tillCIDSCON, after which the new office bearers will take over.

See you in Kochi!

Photoquiz

A 29/m with sickle cell anemia presented with H/O fever with chills – 1 week, evening rise , high grade(T-102F), drycough- 2 days and shortness of breath- 2 days, grade 4. On exam, he was febrile, HR-130/min, BP-140/70, SaO2—94% with 5l O2, Chest – B/L AE, NVBS all over except right base- bronchial breathing, B/L coarse crackles andrhonchi present. Investigations showed TC-25400 HB-11.4 ESR-39. PCT – 0.11ng/ml. He did not improve, WBC was19,000 and oxygenation worsened despite 4 days of ceftriaxone and clarithromycin.

Fig 1: CXR on admission, Fig 2: CXR after 4 days of antibiotics, Fig 3: CT chest after 4 days of antibiotics

What is your diagnosis?

ID NEWS

West Nile Virus in India

Contributed by Dr R Surendran, Dr Ashwini Tayade

A six year old boy from Malappuram district, Kerala, admitted to the intensive care unit of Kozhikode Medical CollegeHospital, was diagnosed to be infected with West Nile Virus to which he succumbed on 18 March 2019 (News Item -Outlook 19 March 2019). This is claimed to be the first case of fatality due to the illness reported from India, thoughthere had been several reports of prior existence of this disease.

WNV is a member of the genus flavivirus belonging to the Japanese encephalitis virus (JEV) antigenic complexunder family flaviviridae. Mosquitoes are the principal vectors of WNV. Various Culex species are found to act asvectors in different geographical regions. The virus is maintained in a bird-mosquito cycle in nature. It was firstisolated during 1937 in the West Nile district of Uganda from a patient suffering from mild illness. WNV has beenreported from many countries. Several epidemics have been reported from middle East, Africa and Israel and theWNV is endemic in Middle East, Africa and Southwest Asia. The virus spread to the USA for the first time in the1990s and causes annual outbreaks there in summer.

In India, presence of West Nile antibodies in humans was first reported from Bombay by Banker in 1952. During apost sero-epidemiological study, Risbud et al, detected WNV neutralizing antibodies among humans at South Arcotdistrict of Tamil Nadu. WNV has been isolated from sporadic cases of encephalitis and mosquitoes. It has beenhypothesized that there is an intermingling of JEV and WNV at the south Indian peninsular region.

WNV is highly prevalent in India and usually causes a mild, non-fatal dengue like illness in humans. However, febrileillness in epidemic form and clinically overt encephalitis cases were observed in Udaipur area of Rajastan, Buldhana,Marathwada and Khandesh districts of Maharashtra. WNV neutralizing antibodies (about 20-30%) have beendetected in human sera collected from Tamil Nadu, Karnataka, Andhra Pradesh, Maharashtra, Gujarat, MadhyaPradesh, Orissa and Rajastan. Serologically confirmed cases of WNV infections were reported from Vellore andKolar districts during 1977, 1978 and 1981 (IJMR 2003).

An investigation of outbreak of 208 cases of AES in Kerala in 2011 by Anukumar et al. has found that total of 47patient samples were positive for in-house JE IgM capture ELISA and WNV IgM capture ELISA. Serum neutralizationassay result revealed that 32 of 42 (76.19%) sera were positive for WNV neutralization antibodies. WNV was isolatedfrom a clinical specimen. Phylogenetic analysis of WNV envelope gene revealed 99% homology with RussianLineage 1 WNV. They reported 2 deaths in their study (J Clin Virology 2014). Testing for West Nile virus is availableat the National Institute of Virology, Pune, and National Institute of Virology, Allapuzha. Facility for xeno-diagnosiswith respect to infection among vectors is available at the Vector Control Research Centre (VCRC), Kottayam.

Infection with West Nile virus is either asymptomatic (no symptoms) in around 80 percent of infected people, or canlead to West Nile fever or severe West Nile disease. About 20 percent of people who become infected with West Nilevirus will develop West Nile fever. Symptoms include fever, headache, tiredness, and body aches, nausea, vomiting,occasionally with a skin rash (on the trunk of the body) and swollen lymph glands.

Treatment is supportive for patients with neuro-invasive West Nile virus, often involving hospitalization, intravenousfluids, respiratory support, and prevention of secondary infections. No vaccine is available for humans.

No WNV vaccines are licensed for use in humans. In the absence of a vaccine, prevention of WNV disease dependson community-level mosquito control programs to reduce vector densities, personal protective measures todecrease exposure to infected mosquitoes, and screening of blood and organ donors.

ID NEWS

Anthrax, Odisha and the role of elephants

Contributed by Dr R Surendran, Dr Ashwini Tayade

Article Link: https://royalsocietypublishing.org/doi/full/10.1098/rspb.2019.0179

Fear of an anthrax and diarrhoea outbreak has triggered panic in Dasmantpur area of Odisha as 3 people have diedof it. India has a high burden of anthrax, with some locations experiencing annual or near annual outbreaks ofdisease, with up to a dozen cases reported in a year

This study has provided the first country-wide predictions of anthrax suitability for India and has found that thissuitability is strongly associated with the elephant–livestock interface as represented by the presence of livestockacross the spectrum of the elephant niche.

Interventions directed at preventing transmission at this specific interface may be an important step toward avertingoutbreaks of anthrax. Moreover, while not as impactful as the elephant–livestock interface, the concurrent influenceof historical forest loss lends further support to the potential importance of anthropogenic ecotones in the ongoingtransmission of anthrax in India. The high suitability corridors running from Andhra Pradesh to West Bengal in theeast, and the forest fringes of the Western Ghats from Kerala to southern Maharashtra in the west would beappropriate targets for improved biosurveillance, as well as deeper field investigations of anthrax disease ecology.So preserve your forests to prevent not just climate change but anthrax!

Fig 1 - Representation of the elephant-livestock interface in anthropogenic ecotones, Fig 2 - Distribution of Anthraxoutbreaks

ID NEWS

Influenza H1N1 update

Contributed by Dr R Surendran, Dr Ashwini Tayade

More than 2500 cases of seasonal [influenza A(H1N1)], also known as swine flu, were recorded in just one week inIndia, between [24 Feb-3 Mar 2019], according to a report by the National Centre for Disease Control [NCDC]. It alsoshows that 17,366 cases and 530 deaths were recorded in the country until [3 Mar 2019].

The number of cases reported in the 1st 2 months of the year [2019] is much higher than the 14,992 cases recordedin the entire year in 2018. Last year [2018], 1103 deaths had been reported. The high number of cases this year[2019] could be because more people are getting tested.

Of the 530 deaths that have been reported so far, 254 were from just 2 states -- Rajasthan and Gujarat. These 2states have also reported the highest number of cases. So far, 4317 people in Rajasthan and 3408 people in Gujarathave tested positive for H1N1. With 3134 cases, Delhi is not far behind. Of the total, 408 cases were reported thisweek [week of 4 Mar 2019] in the national capital. This shows a declining trend, with the highest increase over aweek being 609 cases reported 2 weeks ago.

JOURNAL REVIEW

What is the overall long term impact of colonization with MDR GNB – not much!

Clin Infect Dis. 2019 Feb 1;68(4):641-649 Contributed by Dr Abi Manesh

Long term outcomes in patients with MDR GNB colonization are not clear. We know that colonization with MDR GNBwithin the hospital is associated with high risk of invasive infections during the hospital; stay and probablyimmediately after that especially among critically ill patients and patients affected with cancer. This interestingSwedish study evaluates the long term risk of blood stream infections after colonization with extended spectrum β-lactamase–producing Enterobacteriaceae (EPE). Subjects were followed from their first EPE finding in feces (n =5513) or urine (n = 17189) up to 6 years. The effects of co-morbidity, sociodemography, and outpatient antibioticdispensation on EPE-BSI risks were assessed. The EPE-BSI risks were compared to those of 45161 matchedpopulation–based reference subjects. The cumulative 6-year EPE-BSI incidences were 3.8%, 1.6%, and 0.02% in theurine, feces, and reference cohorts, respectively. The incidences decreased exponentially after the first month.Among EPE-exposed subjects, urological disorders were associated with the highest adjusted cause–specifichazard ratio (aCSHR) for subsequent EPE-BSIs (3.40, 95% confidence interval 2.47–4.69) closely followed byhematological and solid organ malignancies. Antibiotics with selective activity against gram-negative bacilli—butmostly not EPE (trimethoprim-sulfamethoxazole, fluoroquinolones, oral cephalosporins, and penicillins withextended spectrums) were associated with doubled EPE BSI risk. The following are important take homes I feel:

1. MDR GNB colonization screening significantly correlates with invasive BSIs within the hospital stay orimmediately after that especially in critically ill and neutropenic patients. The long term impact appears to benot much.

2. The bulk of the BSIs are contributed by urological disorders with colonization – not surprising and verydifficult group to intervene.

3. Any antibiotic use is bad – not only those with activity against ESBLs to induce resistance.

JOURNAL REVIEW

Attempt to shorten latent TB treatment

N Engl J Med. 2019 Mar 14;380(11):1001-1011 Contributed by Dr Sowmya Sridharan, Dr Abi Manesh

Nine months of isoniazid, isoniazid and rifapentine administered weekly for 3 months, 3 months of daily isoniazidand rifampin, and 4 months of daily rifampin monotherapy are the various options for treatment for Latent TBinfection. The investigators in this non inferiority trial evaluated the efficacy and safety of a 1-month regimen of dailyrifapentine plus isoniazid (1-month group) with 9 months of isoniazid alone (9-month group) in HIV-infected patientswith or without latent TB infection living in areas of high tuberculosis prevalence.  The primary end point was the firstdiagnosis of tuberculosis or death from tuberculosis or an unknown cause.

The primary end point was reported in 32 of 1488 patients (2%) in the 1-month group and in 33 of 1498 (2%) in the 9-month group, for an incidence rate of 0.65 per 100 person-years and 0.67 per 100 person-years, respectively (ratedifference in the 1-month group, −0.02 per 100 person-years; upper limit of the 95% confidence interval, 0.30).Serious adverse events occurred in 6% of the patients in the 1-month group and in 7% of those in the 9-month group(P=0.07). The percentage of treatment completion was significantly higher in the 1-month group than in the 9-monthgroup (97% vs. 90%, P<0.001).

This data shows that shorter 1 month duration treatment with rifapentine and isoniazid will be a good option amongHIV infected patients with LTBI. This needs evaluation in HIV uninfected populations as well.

JOURNAL REVIEW

Minocycline for CRAB infections – Watch out!

J Antimicrob Chemother. 2019 Feb 1;74(2):295-297 Contributed by Dr Abi Manesh

Minocycline has received a lot of recent attention in view of escalating AMR and paucity of good options againstcarbapenem resistant Acinetobacter infections. They appear to penetrate lung and bone tissues well and have goodoral bioavailability. Overall, during recent decades the activities of all tetracyclines against A. baumannii have beeninterpreted using MIC breakpoints of MIC ≤4 mg/L for susceptibility and MIC ≥16 mg/L for resistance by CLSIguidelines. On the other hand, EUCAST has not issued minocycline breakpoints for A. baumannii. Preliminary studieshave confirmed that minocycline is an AUC/MIC-driven agent.

A pharmacodynamic target (PDT) of free AUC/MIC equal to 20–25 is required for A. baumannii and the  free AUC fora 200 mg dose of minocycline should be 18–40 mg·h/L. To achieve this the MIC values should be less than 1–2 mg/L much lower the current cutoffs. Also when the authors attempted Monte Carlo simulation for many dosingstrategies (100mg, 200mg, 400mg) and show that a 200mg daily dose of minocycline only had an 85% probability oftarget attainment (fAUC/MIC >25) at an MIC of 0.5mg/L, and even 400mg daily yielded 0% PTA at an MIC of 4mg/L.

In simpler terms the following are the potential conclusions:

1. The CLSI breakpoints for minocycline against A. baumannii are rather liberal. If one has to use the agent forserious infections consider a high dose – more than or equal to 400mg per day.

2. Always get an MIC when you are attempting to use minocycline for CRAB infections.

JOURNAL REVIEW

INSTIs for treatment experienced HIV 2 – Take note

J Antimicrob Chemother. 2019 Feb 11 Contributed by Dr Abi Manesh

The authors who manage a large cohort of Spanish patients with HIV 2 infection present their experience with use ofINSTIs in their patients with rather surprising results. They identified 44 HIV-2-infected individuals who had initiatedART with INSTI-based regimens among their cohort of 354 patients. Among them 18 were antiretroviral-naive and 26had virological failure under another regimen at the time of INSTI initiation. All patients received two NRTIs, and halfof the 26 patients given an INSTI as rescue therapy also received a boosted protease inhibitor.  Clinicians prescribedraltegravir in 28 cases, dolutegravir in 9 cases, and elvitegravir in 7 cases.

After a median follow-up of 12 months, 16 (88.9%) individuals achieved and/or maintained undetectable HIV-2viraemia. Virological failure under INSTI-based therapy was recognized in 15 HIV-2-infected individuals, 2 being(11.1%) drug-naive and 13 (50%) treatment-experienced. The mean time between initiation of INSTI-based therapyand genotypic analysis at failure was 42 weeks (range 16–88). A total of 12 individuals developed INSTI-associatedresistance mutations along with other PI mutations as well.

One patients on dolutegravir based therapy developed R236K plus E92G mmutations conferring resistance. Data onpatient adherence was not provided in the study. In conclusion, one should be cautious in using INSTIs especiallyraltegravir among treatment experienced HIV 2 infected patients due to potential low barrier to resistance.

JOURNAL REVIEW

A Trial of a Shorter Regimen for Rifampin-Resistant Tuberculosis.

N Engl J Med. 2019 Mar 28;380(13):1201-1213 Contributed by Dr Abi Manesh, Dr Sowmya Sridharan

The shortened 9 to 11 month MDR TB regimen were proposed as an effective strategy to decrease the prolongedduration drug therapy and side effects of conventiontional long term (18-24 months treatment). This was based onuncontrolled cohort studies from domiciliary treatment model from Bangladesh with poor representation of HIVinfected patients. This strategy has been endorsed by the WHO in 2012, 2016 and 2018. STREAM 1 is a large wellconducted RCT which explored this in a real world setting with patients recruited from 4 countries (South Africa,Ethiopia, Mongolia and Viet Nam). The PICOT statement for the RCT is as follows. P – Pulmonary MDR TBdiagnosed by Xpert with no FQ / AG resistance by line probe I – modified Bangladeshi shortened MDR regimen for 9-11 months C – Regular local MDR regimen typically extending for 18-24 months O – Favourable outcome: Culture –ve for MTB at 132 weeks (2.5 yrs) T – 2012-15 in 4 countries Study type: Non inferiority, 2:1 RCT open label, stratifiedaccording to HIV status and trial site

The intervention arm received 9 to 11 months of moxifloxacin (high- dose), clofazimine, ethambutol, andpyrazinamide administered over a 40-week period, supplemented by kanamycin, isoniazid, and prothionamide in thefirst 16 weeks

The Favorable status was reported in 79.8% of participants in the long-regimen group and 78.8% of those in theshort-regimen group - a difference, with adjustment for human immunodeficiency virus status, of 1.0 percentagepoint (95% confidence interval [CI], −7.5 to 9.5) (P=0.02 for noninferiority) showing the shorter regimen was noninferior. The following caveats are worth mentioning – microbiological failures were higher among the shorter groupand HIV infected had higher mortality in the shorter group (18 of 103 (17.5%) in the short group died and 4 of 50(8.0%) in the long group (hazard ratio 2.23; 95% CI, 0.76 to 6.60).

In summary, STREAM 1 marks an important progress in MDR TB treatment, especially in a programmatic approachsetting or when Hain second line reports indicate no resistance to quinolone or injectable. Slightly highermicrobiological failures, increased mortality among HIV infected and increased QTc in the shorter treatment arm areconcerning.

Guideline watch

International Consensus Guidelines for the Optimal Use of Polymyxins: Polymyxin B is recommended overcolistin (polymyxin E) in most situations with the exception of urosepsis and intrathecal therapy, wherecolistin is preferred. [Pharmacotherapy. 2019 Jan;39(1):10-39]

WHO updates TB guidelines: [Link]

Answer to the photoquiz

Peripheral smear on admission showed many sickled cells as well as Howell-Jolly bodies (Fig 1).

Acute chest syndrome complicating sickle cell disease was diagnosed in view of lack of improvement on antibioticsand peripheral smear. He underwent red cell exchange transfusion and high flow oxygen with NIV, improved and wassubsequently discharged. Post exchange transfusion smear is shown (Fig 2).

Acute chest syndrome (ACS) is the most common form of acute pulmonary disease in patients with SCD, occurringin almost one-half of patients, and is a leading cause of death if diagnosed late and allowed to progress. ACS isdefined as a new segmental opacity on chest radiograph accompanied by fever and/or respiratory symptoms in apatient with SCD. Etiologies include pulmonary vaso-occlusion and ischemia, pneumonia, fat embolization andthrombosis. Clinically it is almost indistinguishable from CAP, especially as CAP and sepsis caused by encapsulatedorganisms like pneumococci are common in the sickle population. Prompt recognition, oxygen therapy and red cellexchange transfusion can be life saving.

Fig 1: Peripheral smear at hospital admission, Fig 2: Peripheral smear after exchange transfusion

Case provided by Dr Sowmya Sridharan