Clinical Infectious Diseases SocietyNewsletter : June 2019

Website: www.cidsindia.org Volume 6, Issue 6, June 2019

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

Editor's note

Dear colleagues Hope all of you have registered for CIDSCON and encouraged your juniors to send in abstracts. Theconference website www.cidscon.in has details. The image at the end of the newsletter can be used for publicity inyour talks/ notice boards etc.

See you in Kochi!

New Members

CIDS welcomes the following new members

S.No Name City

1 Dr. Tehmina Manek Bharucha Mumbai

2 Dr. Sanjay Verma Chandigarh

3 Dr. Sujata Vivek Rege Pune

4 Dr. Vikas Deswal Vellore

5 Dr. Sunil Kumar Mahavar Jaipur

6 Dr. K.V. Somasekhar Reddy Nandyal

7 Dr. M.Vivekanandan Puducherry

8 Dr. Deepak Kumar Warkade Jabalpur

9 Dr. Aijaz Nabi Koul SriNagar

10 Dr. Sarita Mohapatra New Delhi

11 Dr. Gagandeep Singh New Delhi

12 Dr. Suhas Nirkhiwale Indore

13 Dr. Prerna Aggarwal Chandigarh

14 Dr. Gursimran Kaur Mohi Karnal

15 Dr. Reema Nath Dibrugarh

16 Dr. Sayan Bhattacharyya Kolkata

17 Dr. Raksha K Bangalore

18 Dr. Saurabh Pandey Lucknow

19 Dr. Parikshit Prayag Pune

20 Dr. Yogesh Kumar Gupta Jaipur

21 Dr. Shareek PS Trivandrum

Photoquiz

A 45-year-old Nepali lady living in Kathmandu presented with h/o painful subcutaneous nodules. She also revealedmigratory chest pain, recurrent fever in the evenings, and night sweats. Laboratory investigations showed a totalleucocyte count of 11300/μl with marked eosinophilia (41%; absolute eosinophil count 4633/μl), mild anemia (Hb10.3 gm%), a normal platelet count, and a raised ESR of 87 mm/h. She was found to have bilateral pleural effusionalong with pericarditis with pericardial effusion. CT scan abdomen shows the following (Figure A-E).

On reviewing the records, she had received with ivermectin for 2 days and diethylcarbamazine (DEC) for 21 days withonly a partial response in Nepal.

Figure 1: (A) X-ray showing pleural effusion & pericardial effusion, (B) CT image showing pleural and pericardialeffusions, (C) migratory skin lesion on the trunk, (D-E) CT image showing multiple hypodense lesions and tracks

What is your diagnosis?

ID NEWS

Primary Amebic Encephalitis in Kerala

Contributed by Dr Sowmya Sridharan

A 10-year-old girl from Malappuram district,Kerala has died of primary amoebic meningoencephalitis, an infection ofthe brain caused by Naegleria fowleri.

A similar case had been earlier reported from Alappuzha. Malappuram District Medical Officer said that the HealthDepartment would issue an alert to be careful against venturing into contaminated water bodies and claimed that arapid response team had been formed to look into other encephalitis and meningitis cases. Doctors had been told toreport all atypical fever cases to the team to spot potential epidemics. A treatment protocol would soon be out, sheadded.

PAM is caused by Naegleria fowleri, a free-living amoeba. This amoeba is commonly found in lakes, rivers, and soil.It infects people when contaminated water enters their body through the nose, from where it reaches the brain andcauses primary amoebic meningoencephalitis. People do not become infected from drinking contaminated water.Only 4 people in the U.S. out of 145 have survived infection from 1962 to 2018. Severe frontal headache, fever,nausea, and vomiting are the symptoms in the primary stage. Later, the patient may experience stiff neck, seizures,altered mental status, hallucinations, and slip into a coma. The mortality rate is comparatively high in this type ofinfection.

Signs and symptoms of Naegleria fowleri infection are clinically similar to bacterial meningitis, which lowers thechances of initially diagnosing PAM. Symptoms start 1-9 days (median 5 days) after swimming or other nasalexposure to Naegleria containing water. People die 1-18 days (median 5 days) after symptoms begin. PAM isdifficult to detect because the disease progresses rapidly so that diagnosis is usually made after death.

JOURNAL REVIEW

Ultra short therapy for native joint septic arthritis

Ann Rheum Dis. 2019 Apr 16 Contributed by Dr Abi Manesh

It’s gratifying to see many randomized trials being done in the area of osteo-articular infections. We had OVIVA,which propelled a practice-changing shift from intravenous to oral medications. However, the duration of antibiotictherapy remained long in both arms in OVIVA. Here, the authors attempt to shorten therapy in native joint septicarthritis. This single Swiss center RCT randomized patients into 2 week and 4 week arms after adequatedebridement following native joint septic arthritis (NJSA). The physicians could decide whether the treatment wasall oral, mix of intravenous (IV) and oral or all IV. Their outcome was remission of infection defined by absence of anyclinical, lab, or radiographic findings 2 months after completing treatment. 154 patients were randomized into twoarms of 77 each. Most of the joints involved were small joints of the hand [finger (n=95); wrist (n=3); knee (n=14);shoulder (n=7); ankle (n=3); elbow (n=1); hip (n=1); metatarsal (n=28)]. This is rather unusual and the origin ofinfections also varied widely [surgical site infections (n=12); animal bites or scratches (n=52); intravenous drugabuse (n=9); direct trauma (n=48); unknown (n=47)].

Of the 154 episodes in the ITT population, 148 (96%) were microbiologically cured after an active median follow-upof 0.5 years (IQR: 0.3–1.1 years) and a passive median follow-up of 2.2 years (IQR: 1.6–2.8 years). Among the sixpatients who ultimately failed on therapy, three patients (one in the 4-week arm, and two in the 2-week arm) finallyrevealed new pathogens completely different from the initial agents. (S. aureus in two cases and Streptococcuspyogenes in one). The median time of recurrence was 32 days.

While generalizing this study may be difficult in view of predominant small joint NJSA, it does provide a platform toattempt shortening therapy in NJSA provided underlying osteomyelitis is carefully ruled out.

JOURNAL REVIEW

No more one size fits all in sepsis – the sepsis phenotypes!

JAMA. 2019 May 19 Contributed by Dr Abi Manesh

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection by the2016 SCCM/ESICM task force. Sepsis pathogenesis is incredibly complex and many attempts to reduce mortalityhave failed. One of the puzzling questions is whether these interventions are beneficial in a particular subset ofpatients while may be harmful or not beneficial in others. This landmark study uses big data and machine learningalgorithms to pick out specific phenotypes of patients with sepsis.

The authors identified 29 patient parameters at admission and evaluated their significance for 28-day mortality in aderivation cohort of 20189 patients. This was again validated in a large cohort. Based on these the authorsproposed four different phenotypes of septic patients. (28 day mortality within brackets)

1. alpha (α): 1/3 patients; fewest abnormal labs, organ dysfunction, in-hospital death rate (5%)2. beta (β): Identified in 27% of patients; older age, more chronic illness, and kidney dysfunction (13%)3. gamma (γ) roughly one in four patients; distinguished from β by having elevated inflammation and primary

pulmonary dysfunction (24%)4. delta (δ): Identified in 13% of patients; least common and most deadly phenotype; characterized by liver

dysfunction and shock and the highest in-hospital mortality (32%)

The authors also showed that these phenotypes had distinct pro-inflammatoy cytokine signature as well. Finally theauthors introduced these phenotypes in various studies which evaluated many interventions. For example, theystudied that the ProCESS trial which evaluated early goal directed therapy in sepsis and concluded that it isineffective. The authors showed that the EGDT could be a very useful intervention in alpha (α) phenotype patients.The importance of this study is multifold – its emphasizes the ability of large data analyses to critically evaluatecomplex diseases like sepsis and identify hidden patterns. It also proposes an explanation why some of the sepsistreatment studies could have failed. Whether these phenotypes would be validated prospectively and can be used toenroll patients in various studies is yet to known.

JOURNAL REVIEW

Early oral switch in GNB bacteremia?

JAMA Intern Med. 2019;179(3):316-323 Contributed by Dr Abi Manesh

Many clinicians are now considering an early switch to oral therapy in patients with Enterobacteriaceae bacteremiawho are responding well to early therapy. This retrospective cohort study adds further evidence to that approach.This retrospective multicenter cohort study included a 1:1 propensity score–matched cohort of 4967 uniquepatients hospitalized with mono-microbial Enterobacteriaceae bloodstream infection at 3 academic medical centersfrom January 1, 2008, through December 31, 2014. Eligibility criteria included appropriate source control measures,appropriate clinical response by day 5, active antibiotic therapy from day 1 until discontinuation of therapy,availability of an active oral antibiotic option, and ability to consume other oral medications or feeding.

Of the 1478 patients included in the analyses, with 739 in each study arm, sources of bacteremia included urine (594patients [40.2%]), gastrointestinal tract (297 [20.1%]), central line-associated (272 [18.4%]), pulmonary (58 [3.9%]),and skin and soft tissue (41 [2.8%]). There were 97 (13.1%) deaths in the oral step-down group and 99 (13.4%) in theintravenous (IV) group within 30 days (hazard ratio [HR], 1.03; 95% CI, 0.82-1.30). There were no differences inrecurrence of bacteremia within 30 days between the groups (IV, 6 [0.8%]; oral, 4 [0.5%]; HR, 0.82 [0.33-2.01]). Theoptions used for oral therapy predominantly included agents with good oral bioavailability like TMP SMX andfluoroquinolones (80%). However, the outcomes were not different even in the group that received low bioavailabilityagents like amoxicillin-clavulanate and cephalosporins. We should probably consider this approach in eligiblepatients with optimal source control.

JOURNAL REVIEW

A novel subgroup of patients with cryptococcal meningitis

Clin Infect Dis. 2019 May 30;68(12):2094-2098 Contributed by Dr Abi Manesh

HIV infected individuals with cryptococcal antigenemia are at high risk of developing cryptococcal meningitis ifuntreated. The progression and timing from asymptomatic infection to cryptococcal meningitis is unclear. In thisinteresting study, the authors describe a subpopulation of individuals with neurologic symptomatic cryptococcalantigenemia but negative cerebral spinal fluid (CSF) studies. The authors evaluated 1201 human immunodeficiencyvirus–seropositive individuals hospitalized with suspected meningitis in Kampala and Mbarara, Uganda. Amongthese, 40% (476/1201) were CrAg negative in blood and excluded from this analysis, all of whom were also cerebralspinal fluid (CSF) CrAg negative. Of those with a positive blood CrAg, 93% (671/725) had positive CSF CrAg andconfirmed cryptococcal meningitis. Of the 54 blood CrAg positive and CSF CrAg negative, 3 were later diagnosed byCSF culture and 2 by polymerase chain reaction with cryptococcal meningitis, 6 were diagnosed withmicrobiologically confirmed tuberculous meningitis, and 43 had neurologic symptomatic cryptococcal antigenemia.Biofire filmarray and Xpert Ultra were used to rule out alternative etiologies in addition to standard techniques.

A significantly higher proportion of participants in the symptomatic antigenemia group had normal CSF white bloodcell counts (<5 cells/µL) compared to the cryptococcal meningitis group (84% vs 64%; P< .01). Similarly, the medianCSF opening pressure was 127 mmH2O (IQR 93–157) in the symptomatic antigenemia group compared to 270mmH2O (IQR, 180–400) in the cryptococcal meningitis group (P < .01). Importantly, the mortality in the symptomaticantigenemia group treated with fluconazole was similar to that of frank cryptococcal meningitis group (31 vs 32%).In summary, the authors elegantly explain a subgroup of patients (third commonest among their HIV infectedpatients with meningitis syndrome) who have cryptococcal antigenemia with no marked CSF abnormalities and CSFcryptococcal antigen is negative.

The authors believe that this is a distinct entity and underline that isolated CSF cryptococcal antigen testing maymiss this diagnosis if a serum cryptococcal antigen was not done alongside. Secondly, CNS cryptococcosis isprimarily a meningoencephalitis where early in infection, yeasts can be present in the brain parenchyma without CSFinvolvement. The authors also suggest that this group of patients should be treated aggressively like cryptococcalmeningitis and not with fluconazole monotherapy.

JOURNAL REVIEW

TLE every alternate day?

AIDS. 2019 Mar 1;33(3):493-502 Contributed by Dr Abi Manesh

There has been a search for more simplified ART regimens as our antiretroviral repertoire widens and patients livehealthier lives. This RCT evaluated the effectiveness of reducing combined TDF/FTC/EFV dosing to alternate daysversus the standard of care regimen (taking one pill daily) on viral load after 48 weeks. Only patients onTDF/FTC/EFV for at least 6 months and with a documented viral load of less than 40 copies/ml were included in thestudy. Importantly patients who had previous virological failure, resistance to any of the medications, or pregnantwere excluded. The non inferiority margin was set at 15%.

A total of 197 patients from an Italian treatment centre were randomised, with 98 allocated to the daily treatmentgroup and 99 allocated to the reduced dosing group. Most of these had acquired HIV through homosexual contact(68%). The median CD4 cell count was 677 (IQR: 525-814), with the median time being on TDF/FTC/EFV 38.3months (IQR: 23.3-55). Patients had been living with HIV for a median of 6.8 years. A high percentage in both groupsshowed successful viral suppression at 48 weeks (97% in the daily group and 94% in the alternate-day dosing group),with a -3% overall risk difference (95% CI: -8.86-2.86%). Virological failure was reported in one patient from the dailydosing group (1%) and three patients from the alternate day dosing group (3%). While the study is interesting, maybe the 15% non inferiority was rather wide and we should await the 96 weeks follow up results before we chose toadopt this result in our practice.

Answer to the photoquiz

The differential diagnosis included fascioliasia, gnathostomiasis and visceral larva migrans. She reported norelevant medical history besides having sustained a traumatic humerus fracture two month before, for which shehad ingested raw live slugs (`Chiple kira´) as a traditional remedy to accelerate the bone healing process.

Echocardiography showed the presence of partial features of pericardial tamponade. Therapeutic pericardiocentesisas well as thoracocentesis revealed exudative effusion with cell count of the pleural and pericardial fluid showing70% and 5% eosinophils, respectively. A skin biopsy of the migratory lesion on the trunk was performed and thesample sent for histopathological and microbiological evaluation (gram stain, AFB stain, Gene Xpert, culture). Thehistopathology report described unspecific panniculitis and the microbiological results came back negative.Additionally performed microscopic stool examinations for parasite eggs and larvae as well as blood microscopy formicrofilaria and testing for circulating filarial antigen was negative. In the absence of cough, no sputum samplescould be investigated at that time.

A serum sample was sent to the Swiss Tropical and Public Health Institute in Basel, Switzerland to performserological testing for tissue invasive parasites. The serum sample was tested with a standard in-house panel ofserological assays consisting of highly sensitive enzyme-linked immunosorbent assays (ELISA) used for screening,followed, if positive, by highly specific immunofluorescence antibody test (IFAT) assays for confirmation, andenzyme-linked immunoelectrotranfer blots (EITB; Western blots).

Following the serological result, repeated induced samples finally detected Paragonimus spp eggs and confirmedthe serological diagnosis.

She was treated with praziquantel (75 mg/kg ) in three divided doses along with colchicine. Patient improved withresolution of fever, pericardial & pleural effusion and eosinophilia.

Final diagnosis: Paragonimiasis (caused by Paragonimus westermani)

Case provided by Dr Neha Gupta