Jurnal Prognosis

JURNAL PROGNOSIS
Dosen Pengampu :
Ns. Nur Isnaini,S.Kep.,M.Kep.
Disusun Oleh Kelompok 10 Kep S1 4A

1. Zikrina Selia Janna 1911020013
2. Santi Anggiani 1911020021
3. Winda Yustiyani 1911020060
PROGRAM STUDI KEPERAWATAN S1

FAKULTAS ILMU KESEHATAN
UNIVERSITAS MUHAMMADIYAH PURWOKERTO
A. JURNAL PROGNOSIS SISTEM PENCERNAAN

1. Judul Jurnal :
A study on acute appendicitis in a tertiary care hospital in Tamil Nadu, India
2. Penulis :
K. Suresh Babu , S. Savitha
3. Latar Belakang Temuan Jurnal :

Apendisitis akut adalah masalah umum pada anak-anak dan kehidupan dewasa awal.
Apendektomi adalah prosedur segera atau darurat untuk mengurangi morbiditas dan mortalitas.
Penelitian ini dilakukan untuk mengetahui profil klinis apendisitis akut dan komplikasi
apendektomi.
4. Metode :
Studi observasi ini dilakukan pada 100 pasien yang didiagnosis apendisitis akut di rumah sakit
perawatan tersier selama tahun 2001 hingga 2002. Profil klinis seperti usia, jenis kelamin,
gejala pasien dan komplikasi pasca operasi dicatat. Semua pasien menjalani operasi usus buntu
dan diikuti pasca operasi.
5. Hasil dan Pembahasan :

Dari seratus pasien, 55% adalah laki-laki dan 45% perempuan. Hampir 71% pasien termasuk
dalam kelompok usia 15-30 tahun. 100% mengalami nyeri perut, 81% mengalami demam dan
75% mengalami muntah. Komplikasi pasca operasi adalah 3%.
6. Kesimpulan Jurnal :
Apendisitis akut yang sangat umum pada kelompok usia yang lebih muda menunjukkan bahwa
setiap kali pasien muda datang dengan nyeri perut akut dapat dianggap apendisitis akut.
Komplikasi apendektomi sangat minimal dan memberikan prognosis yang baik.
7. Kesimpulan Kelompok :
Studi ini menemukan bahwa sebagian besar pasien didiagnosis apendisitis akut penderitanya
berada pada kelompok usia 15 hingga 30 tahun. Nyeri perut berada pada 100%, demam 81%
dan muntah pada 75% .Studi ini menemukan bahwa 3% dari pasien mengalami komplikasi
pasca operasi dan juga sebagian besar disebabkan oleh infeksi luka, luka menganga, obstruksi
mangkuk kecil perekat yang sedikit lebih rendah hingga 11% dalam studi yang dilakukan oleh
Jess P 7,19% dari pasien telah berkembang demam pasca operasi dan mungkin karena berbagai
alasan seperti infeksi saluran kemih atau juga infeksi saluran pernapasan.
B. JURNAL PROGNOSIS SISTEM PERKEMIHAN

1. Judul jurnal :
Associations with and prognostic impact of chronic kidney disease in heart failure with
preserved, mid-range, and reduced ejection fraction.
2. Penulis :
Ida Lofman, Karolina Szummer, Ulf Dahlström, Tomas Jernberg, dan Lars H. Lund.

Hubungan antara CKD dan HFmrEF dan HFpEF kurang dipahami. Tidak ada penelitian yang
secara khusus membandingkan HFpEF, HFmrEF dan HFrEF berkaitan dengan CKD. Laporan
sebelumnya tidak membedakan antara HFpEF dan HFrEF, 11 termasuk pasien yang sangat
dipilih, 1 2 hanya memeriksa prognosis jangka pendek, 1 3 atau CKD diperiksa hanya sebagai
bagian dari beban komorbiditas umum. 1 4 Dengan demikian, tujuannya adalah untuk
melakukan perbandingan CKD komprehensif pertama yang dapat digeneralisasikan dalam
HFpEF, HFmrEF, dan HFrEF sehubungan dengan prevalensi, korelasi klinis dan peran
prognostik jangka panjang.
4. Metode & hasil :

Pasien di Swedish Heart Failure Registry dibagi menjadi tiga kelompok berdasarkan EF ( ≥
50%, 40–49% dan < 0,00 1 untuk semua).Setelah mengecualikan registrasi ulang dan
menerapkan kriteria eksklusi di atas, total 40.230 pasien unik dimasukkan. Dari jumlah
tersebut, 8875 (22%) diklasifikasikan sebagai HFpEF, 8374 (2 1%) sebagai HFmrEF, dan 22 98
1 ( 57%) sebagai HFrEF Setelah penyesuaian, CKD lebih kuat terkait dengan kematian di
HFrEF dan HFmrEF daripada di HFpEF [rasio bahaya (HR) dan interval kepercayaan 95%
(CI); 1. 49 ( 1. 42– 1. 56) dan 1. 5 1 (1. 40– 1. 63) vs. 1. 32 ( 1. 24– 1. 42); P. untuk interaks.
5. Diskusi :
Ini adalah perbandingan CKD yang besar, dapat digeneralisasikan, jangka panjang, dan
komprehensif pertama di HFpEF, HFmrEF, dan HfrEF. menurut jenis HF baru dalam pedoman
ESC HF terbaru. 5 Ada beberapa temuan penting. Hubungan antara CKD dan karakteristik
seperti usia yang lebih tua, jenis kelamin perempuan, dan keparahan gagal jantung yang lebih
besar adalah serupa pada ketiga kelompok. Namun, HFpEF menonjol sebagai perbedaan
dibandingkan dengan HFmrEF dan HFrEF, yang lebih mirip. Pada HFpEF, CKD lebih umum
tetapi kurang penting, dengan hubungan yang lebih lemah dengan kematian, sedikit modifikasi
risiko oleh penanda risiko gagal jantung konvensional, dan dengan kekuatan yang kurang
diskriminatif untuk kematian. Dalam penelitian ini, lebih dari 50% menderita HFrEF. Proporsi
HFpEF dan HFmrEF sama-sama umum, dengan proporsi HFpEF sedikit lebih rendah
dibandingkan penelitian sebelumnya. Studi ini berbeda dari laporan sebelumnya, di mana
HFmrEF telah dikeluarkan atau dikelompokkan dengan populasi HFpEF atau HFrEF. penelitian
ini memberikan deskripsi baru dan rinci tentang kelompok HFmrEF, di mana banyak
karakteristik klinis seperti usia, proporsi wanita, dan hipertensi berada pada kontinum antara
HFpEF dan HFrEF tetapi karakteristik tertentu, seperti penyakit jantung iskemik dan katup
jantung, jelas lebih mirip dengan HFrEF daripada HfpEF.
6. Kesimpulan
CKD dikaitkan dengan kovariat serupa terlepas dari EF. Meskipun CKD lebih sering terjadi
pada HFpEF daripada di HFmrEF dan HFrEF, CKD mungkin memiliki lebih banyak peran
'pengamat' dalam HFpEF, kurang terkait dengan kematian dan dengan diskriminasi prognostik
yang lebih rendah.
C. JURNAL PROGNOSIS SISTEM ENDOKRIN

1. Judul Jurnal :
A Potential Role of Salmonella Infection in the Onset of Inflammatory Bowel Disseases
2. Penulis :
Bárbara M. Schultz , Carolina A. Paduro , Geraldyne A. Salazar , Francisco J. Salazar-
Echegarai , Valentina P. Sebastián , Claudia A. Riedel , Alexis M. Kalergis , Manuel Alvarez-
Lobos * dan Susan M. Bueno , Facultad de Ciencias Biológicas, Departamento de Genética
Molec

Penyakit radang usus (IBD) mencakup serangkaian patologi yang dihasilkan dari respons imun
yang dideregulasi yang dapat memengaruhi bagian mana pun dari saluran pencernaan. Bentuk
IBD yang paling umum dan jelas adalah penyakit Crohn dan kolitis ulserativa. Meskipun
etiologi IBD tidak terdefinisi dengan baik, telah disarankan bahwa faktor lingkungan dan
genetik berkontribusi pada perkembangan penyakit dan interaksi antara kedua faktor ini dapat
memicu patologi. Diet, penggunaan obat, status vitamin D, merokok, dan infeksi bakteri telah
diusulkan untuk mempengaruhi atau berkontribusi pada timbulnya atau perkembangan penyakit
pada individu yang rentan. Infeksi bakteri patogen merupakan faktor kunci yang dapat
mempengaruhi perkembangan dan keparahan penyakit ini. Sini, Salmonella, dapat mendorong
timbulnya IBD karena perubahan permanen pada mikrobiota usus, gangguan penghalang epitel
dan perubahan respons imun usus setelah infeksi.
4. Metode :
Metode deskriptif
MDP menginduksi autophagy dalam sel dendritik, sebuah proses yang membutuhkan
pensinyalan NOD2 yang benar, yang pada gilirannya membutuhkan fungsi ATG16L1 yang
tepat. Protein ini diperlukan untuk fungsi NOD2 dan presentasi antigen yang benar ( 125 ).
Mutasi pada gen ini menghasilkan kerusakan dalam proses autophagy dalam sel dendritik, yang
menunjukkan perdagangan bakteri yang menyimpang dan kegagalan untuk menghasilkan
presentasi antigen pada molekul MHC-II, yang pada gilirannya mendorong pembentukan sel
CD4 + T efektor khusus antigen ( 125 ). Semua cacat ini memungkinkan bakteri bertahan lebih
lama di dalam sel dendritik, menghindari degradasi lisosom untuk waktu yang lama ( 126 ,
127 ) dan untuk menyediakan mekanisme persistensi patogen dan akibatnya inflamasi persisten.
Selain itu, telah dilaporkan bahwa S. Typhimurium menggunakan sel dendritik yang
mengekspresikan CCR7 sebagai jalur untuk bermigrasi dari usus ke MLN
Infeksi Typhimurium dapat memicu peradangan kronis pada individu yang membawa satu atau
lebih cacat yang terkait dengan IBD, mengingat ketidakmampuan pasien ini untuk
membersihkan bakteri di usus dengan benar. Bahkan, S. Typhimurium memiliki gudang faktor
virulensi yang penting untuk menyerang sel inang di epitel usus dan lamina propria yang tidak
dapat dijangkau oleh mikrobiota normal. Selain itu, diketahui bahwa bakteri ini dapat
menyebabkan infeksi persisten pada manusia dan tikus, menunjukkan bahwa pada pasien yang
menunjukkan satu atau lebih cacat genetik yang mempengaruhi perkembangan IBD; mungkin
saja mereka jauh lebih rentan tertular S. Typhimurium dan menyebabkan infeksi yang terus-
menerus. Infeksi permanen sel dengan S. Typhimurium dapat meningkatkan sekresi sitokin pro-
inflamasi oleh sel yang terinfeksi, menghasilkan lingkungan inflamasi di lapisan usus,
mendorong perubahan mikrobiota dan mempromosikan penyakit kronis. Akan relevan untuk
mengevaluasi apakah pasien IBD adalah karier kronis S. Typhimurium di usus.
komunitas mikroba dapat berubah karena usia, nutrisi, proses inflamasi, dan penyakit
gastrointestinal. keberadaan mikrobiota komensal menginduksi ekspresi basal TLR tertentu
(seperti TLR2 dan TLR5), dibandingkan dengan tingkat ekspresi basal yang diamati pada tikus
bebas patogen spesifik dan tikus bebas kuman. Penyakit radang usus ditandai dengan
peningkatan kepadatan bakteri di tingkat mukosa ( 62 , 63 ), serta berkurangnya jumlah bakteri
komensal anti-inflamasi, seperti Gram-positif Firmicutes dan Actinobacteria ( 56 , 64 ). Sebagai
konsekuensi dari disbiosis ini (disregulasi mikrobiota komensal), peningkatan jumlah bakteri
yang berpotensi membahayakan (seperti Enterobacteriaceae) dapat terjadi, menghasilkan
peradangan.
D. JURNAL PROGNOSIS SISTEM IMUNOLOGI
1. Judul Jurnal :
Clinical outcomes in chuldren and adolescents initiating antiretroviral therapy in decentralized
healthcare settings in Zimbabwe
2. Penulis :
Grace McHugh , Victoria Simms , Ethel Dauya , Tsitsi Bandason , Prosper Chonzi , Dafni
Metaxa , Shungu Munyati , Kusum Nathoo , Hilda Mujuru , Katharina Kranzer 1,5 dan Rashida
A. Ferrand *

Perawatan HIV yang terdesentralisasi untuk orang dewasa tampaknya tidak mengganggu hasil
klinis. Perawatan HIV untuk anak-anak menimbulkan kerumitan klinis dan sosial tambahan.
Kami melakukan studi kohort prospektif untuk menyelidiki hasil klinis pada anak-anak berusia
6 tahun - 15 tahun yang mendaftar untuk perawatan HIV di tujuh klinik perawatan kesehatan
primer (Puskesmas) di Harare, Zimbabwe
4. Metode :
Peserta direkrut antara Januari 2013 dan Desember 2014 dan diikuti selama 18 bulan. Tingkat
dan alasan kematian, rawat inap dan kehadiran Puskesmas yang tidak terjadwal dipastikan.
Pemodelan proporsional Cox digunakan untuk menentukan bahaya kematian, kehadiran tidak
terjadwal dan rawat inap.

Kami merekrut 385 peserta, usia rata-rata 11 tahun (IQR: 9 - 13) dan 52% adalah perempuan.
Jumlah CD4 rata-rata adalah 375 sel / mm 3 ( IQR: 215 - 599) dan 77% memulai ART selama
masa penelitian, dengan 64% dari mereka yang memiliki viral load diukur mencapai viral load
HIV < 0,001). Angka rawat inap dan mortalitas rendah (masing-masing 8,14 / 100 orang-tahun
(pyrs) dan 2,86 / 100 thn). Tingkat kehadiran Puskesmas tidak terjadwal tinggi (34.94 / 100
thn), tetapi hanya 7% yang mengakibatkan rawat inap. Penyakit pernapasan adalah penyebab
utama rawat inap, kehadiran yang tidak terjadwal, dan kematian. Jumlah CD4
Meskipun hanya 64% dari peserta yang mencapai penekanan virologi, hasil klinisnya baik dan
tingkat retensi yang tinggi dalam perawatan diamati. Hal ini menunjukkan bahwa di era yang
bergerak menuju perawatan yang dibedakan selain penerapan pengobatan universal, perawatan
HIV yang terdesentralisasi untuk anak dapat dicapai. Intervensi untuk meningkatkan kepatuhan
pada kelompok usia ini sangat dibutuhkan.
Penelitian kami menunjukkan bahwa perawatan HIV yang dipimpin perawat terdesentralisasi
untuk anak adalah mungkin dan menghasilkan hasil klinis yang sebanding dengan yang
dilaporkan pada anak-anak di tempat lain di Afrika bagian selatan [ 20 ]. Penerapan pedoman
WHO 2015 yang merekomendasikan pengobatan universal untuk semua orang yang terinfeksi
HIV, kemungkinan besar menghasilkan peningkatan yang bermakna pada anak yang memenuhi
syarat untuk pengobatan, terutama mengingat cakupan ART yang rendah saat ini. Investasi
yang cukup besar untuk HIV yang sesuai dengan usia. strategi pengujian, pelatihan dan
dukungan untuk penyedia layanan kesehatan primer dan intervensi untuk mendukung
kepatuhan perlu diperkuat untuk mencapai akses universal dan hasil pengobatan yang optimal
di antara anak-anak dan remaja.
International Surgery Journal
Babu KS et al. Int Surg J. 2017 Mar;4(3):929-931
http://www.ijsurgery.com pISSN 2349-3305 | eISSN 2349-2902
DOI: http://dx.doi.org/10.18203/2349-2902.isj20170530
Original Research Article
A study on acute appendicitis in a tertiary care hospital in
Tamil Nadu, India
K. Suresh Babu*, S. Savitha
Department of Surgery, Government Royapettah Hospital, Kilpauk Medical College, Tamilnadu, India
Received: 25 January 2017
Accepted: 04 February 2017
*Correspondence:
Dr. K. Suresh Babu,
E-mail: sures8598@gmail.com
Copyright: © the author(s), publisher and licensee Medip Academy. This is an open-access article distributed under
the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial
use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Background: Acute appendicitis is a common problem in children and early adult life. Appendicectomy is immediate
or emergency procedure to reduce morbidity and mortality. The present study was conducted to find out clinical
profile of acute appendicitis and complications of appendicectomy.
Methods: This observational study was conducted among 100 patients diagnosed as acute appendicitis in tertiary care
hospital during the year from 2001 to 2002. The clinical profile like age, sex, symptoms of the patients and post-
operative complications were recorded. All patients underwent appendicectomy and followed post operatively.
Results: Out of hundred patients, 55% were male and 45% were female. Nearly 71% of the patients belonged to the
age group of 15-30 years.100% had pain abdomen, 81% had fever and 75% had vomiting. The post-operative
complication was 3%.
Conclusions: Acute appendicitis is very common in younger age groups shows that whenever young patients present
with acute abdominal pain may be considered acute appendicitis. The complication of appendicectomy is very
minimum and gives good prognosis.
Keywords: Appendicitis, Post-operative, Retrocaecal
INTRODUCTION
The lifetime prevalence of acute appendicitis is
approximately 7%.2 Acute appendicitis is the most
common cause of acute abdomen requiring surgical
The vermiform appendix is considered to be a vestigial intervention during childhood, accounting for 1-8% of
organ, its importance in surgery due only to its propensity children who present to the paediatric emergency room
for inflammation which results in clinical syndrome with acute abdominal pain.3
known as acute appendicitis. Acute appendicitis is a
common problem among older children and young adults.
This problem occurs sudden in onset and warrants the
patients to seek immediate health care. The present study was conducted to find out the common
symptoms, certain demographic profile and post-operative
complication of acute appendicitis which may help in
diagnosing and management of acute appendicitis.
Occasionally the perforation of appendix may produce
life threatening situations. Several studies reported male
predominance than female. Many patients have typical
METHODS
clinical symptoms like abdominal pain, fever and
vomiting. Most of the times Appendicectomy reduces
morbidity and mortality. In United States, 250,000 cases
of appendicitis are reported annually.1 Descriptive study was done at government Royapettah
Hospital, Kilpauk Medical College, Tamil Nadu, India.
International Surgery Journal | March 2017 | Vol 4 | Issue 3 Page 929

Total 100 100
100 Patients with diagnosis of acute appendicitis were The position of the appendix during the surgery nearly
taken for the study. Study duration was 2001 to 2002. 82% of the position of appendix was retrocaecal (Table
2). 94% of appendixes were inflamed and 4% were
perforated and 2% were gangrenous. About 19% of the
patients developed fever after the surgery and 3% were
The study was conducted among randomly selected 100
developed post-operative complications. Among 3
patients with acute appendicitis diagnosed with the help patients one patient had wound infection, one patient had
of clinical examination and other investigation like wound infection and wound gaping and another patient
ultrasonogram. The clinical symptoms were recorded, had wound infection, wound gaping and small bowl
certain demographic profile like age and sex were obstruction. All these patients were treated appropriately
collected. All the 100 patients were underwent and discharged in good condition. No delayed
appendicectomy and followed in the hospital for complications were observed in follow up of the patients.
immediate complication and also followed for remote The mortality was not observed in this study. The
complications. All patients have received 3 to 7 days proteus organisms, pseudomonas organisms were found
antibiotics, and regular treatment. Appropriate treatment in wound infections.
was given wherever complication was noted.
RESULTS
Out of 100 patients, 55% were male and 45% were

female. Nearly 71 % were belonged to the age group of
15-30 (Table 1). All 100 patients that is 100% had pain
abdomen. About 81% had fever and 75% had vomiting.
Table 1: Distribution of age and sex of the study
population (N = 100).
Age (years ) Male Female Total Percentage
0-14 06 06 12 12
15-30 41 30 71 71
31-46 07 08 15 15
46-61 01 00 01 01
Above 62 00 01 01 01
Total 55 45 100 100
Table 2: Distribution of position of appendix.
Position Number Percentage

Retrocaecal 82 82
Pelvic 11 11
Postileal 03 03
Preileal 02 02
Paracolic 01 01
Sub caecal 01 01
The limitations of the study was size of the sample which
is little low and if larger sample may show minimal
variations.
DISCUSSION
ACKNOWLEDGEMENTS
The present study was conducted among 100 patients
diagnosed as acute appendicitis and observed that male
were more in number (55%) than female shows that male The authors would like to thank Dr. P. K. Govindarajan,
predominance in acute appendicitis is one of the notable Professor and Head, Community Medicine RMMC for
factor which is similar to 60% in male in a study his guidelines in publication of the paper
conducted by Chaudhar YP et al in Maharastra, India.4
Funding: No funding sources

This study has found out that most of the sufferer were in
the age group of 15 to 30 years which is supported by a Conflict of interest: None declared
study conducted by Pralhad Y. 4 The present study has
observed that Pain abdomen was in 100%, fever was in Ethical approval: The study was approved by the
81% and vomiting in 75% of the patients which is almost institutional ethics committee
close to 99%, 76% and 56% respectively, a study
conducted by Kamath P et al.5
REFERENCES
The position of appendix was also observed in this study
and found out that 82% of the appendix were in retrocecal
in position that means most of the time appendix present 1. Lohar HP. Epidemiological aspects of appendicitis
in retrocaecal and 11% in pelvic in position which is in a rural setup. Medical J DY Univ. 2014;7(6):753-
supported by 57% retrocecal and 25% pelvic a study 7.
conducted by Salwe NA.6 2. Brunicardi FC, Andersen DK, Billiar TR. The
appendix. In: Schwartz's principles of surgery. 9 th
Edition. New York, NY: McGraw-Hill. 2012:2043-
This study has noticed that 3% of the patients had 67.
postoperative complication and also were mostly due to
wound infection, wound gaping, adhesive small bowl 3. Rothrock SG, Pagane J. Acute appendicitis in
obstruction which is little lower to 11% in a study children: emergency department diagnosis and
conducted by Jess P 7.19% of the patients have developed management. Ann Emerg Med. 2000;36:39-51.
fever postoperatively and may be due to various reasons
like urinary tract infection or respiratory tract infections
also.7
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4. Chaudhari YP, Jawale PG. Prevalence of

appendicitis at surgery inpatient department of a region. Int J Advanced Physiology Allied Sci.
tertiary care hospital: a descriptive study. Int Med J.
2014;2(1):31-41.
2015;2(11):768-70.
5. Kamath P. A clinico pathological study of 7. Jess P, Bjerregaard B, Brynitz S, Christensen J,

appendisectomy cases in a tertiary care hospital in Kalaja E. Acute appendicitis: prospective trial
South India. Indian J Applied Research. concerning diagnostic accuracy and complications.
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6. Salwe NA, Kulkarni PG, Sinha RS. Study of
morphological variations of vermiform appendix
and caecum in cadavers of western Maharashtra Cite this article as: Babu KS, Savitha S. A study
on acute appendicitis in a tertiary care hospital in
Tamil Nadu, India. Int Surg J 2017;4:929-31.
European Journal of Heart Failure (2017) 19, RESEARCH

1606–1614 doi:10.1002/ejhf.821
ARTICLE
Methods
and results
Associations with and prognostic

impact of chronic kidney disease
in heart failure with preserved,
mid-range, and reduced ejection
fraction
1 1 2 3
Ida Löfman *, Karolina Szummer , Ulf Dahlström , Tomas Jernberg ,
4
and Lars H. Lund
1 Department of Cardiology, Karolinska University Hospital, Huddinge, Institution of Medicine (H7), Huddinge; Karolinska Institutet, 141 86, Stockholm, Sweden; 2
Department of Cardiology
and Department of Medical and Health Sciences, Linköping University Hospital, Linköping, Sweden; 3Department of Clinical Sciences, Danderyd University Hospital, Karolinska Institutet, Stockholm,
Sweden; and 4Department of Medicine, Section of Cardiology, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
Received 24 November 2016; revised 4 February 2017; accepted 21 February 2017 ; online publish-ahead-of-print 29 March 2017
Aims As the role of chronic kidney disease (CKD) in different types of heart failure (HF) is poorly understood,
our aim was to compare CKD in HF with preserved (HFpEF), mid-range (HFmrEF), and reduced
ejection fraction (HFrEF) with regard to prevalence, associations and prognostic role.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
...
Patients in the Swedish Heart Failure Registry were divided into three groups based on EF (≥50%, 40–49%
2
and <40%). CKD was defined as an estimated glomerular filtration rate ≤60 mL/min.1.73 m . Associations
between covariates and CKD and between CKD and mortality were assessed with multivariable regressions.
Of 40 230 patients, 8875 (22%) had HFpEF, 8374 (21%) had HFmrEF, and 22 981 (57%) had HFrEF, with a
CKD prevalence of 56%, 48%, and 45%, respectively. Associations between covariates and CKD were
similar in all EF groups. One-year mortality with vs. without CKD was 23% vs. 13% in HFpEF, 22% vs. 8% in
HFmrEF, and 23% vs. 8% in HFrEF (P < 0.001 for all). After adjustment, CKD was more strongly associated
with death in HFrEF and HFmrEF than in HFpEF [hazard ratio (HR) and 95% confidence interval (CI); 1.49
(1.42–1.56) and 1.51 (1.40–1.63) vs. 1.32 (1.24–1.42); P for interaction <0.001]. In receiver operating
characteristic (ROC) analyses, CKD was also a stronger predictor of death in HFrEF and HFmrEF than in
HFpEF [area under the curve (AUC) 0.699 (0.689–0.709) and 0.700 (0.683–0.716) vs. 0.629 (0.613 –0.645)].
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
...
Conclusion CKD was associated with similar covariates regardless of EF. Although CKD was more common in
HFpEF than in HFmrEF and HFrEF, it may have more of a ‘bystander’ role in HFpEF, being less
associated with mortality and with lower prognostic discrimination.
........................................................................................................
..
Keywords Heart failure • Preserved ejection fraction • Mid-range ejection fraction • Chronic kidney
disease • Mortality • Prognosis
Introduction
in HF with reduced ejection fraction (HFrEF). 4 Similarly,
...................
numerous trials in HFrEF have established the efficacy

and safety of neuro-hormonal antagonist drugs, and the
Chronic kidney disease (CKD) is common in heart failure (HF) criteria for renal function and potassium levels are
and is associated with worse outcomes. 1,2 The complex available to guide clinicians in prescribing and titrating
haemodynamic and neurohormonal relationship between the these drugs.5
heart and kidney constitutes the cardiorenal syndrome. 3 The
increased mortality with CKD and worsening renal function has In contrast, HF with preserved ejection fraction (HFpEF),
been well described variably defined as ejection fraction (EF) >40–55%, is a
*Corresponding author. Tel: +46708744502, Fax: +46858583124; Email: ida.haugen-lofman@sll.se
© 2017 The Authors
European Journal of Heart Failure © 2017 European Society of Cardiology

Associations with and prognostic impact of CKD in HF 1607
... ...
The registry includes variables concerning baseline description of
heterogeneous syndrome that remains poorly understood and
.. ..
patients, including risk factors, history of heart disease, cardiac diag-
5,6
nostics and interventions, medication, and laboratory tests.
. ... ... ... ..

without evidence-based treatment. Heart failure with mid-range
.
Serum creatinine was obtained at discharge for hospitalized patients
ejection fraction (HFmrEF) is increasingly viewed as a separate
...
and at the closest date preceding an outpatient visit. Glomerular
category7,8 and was defined as a distinct EF 40–49% phenotype
... ...
filtration rate was estimated (eGFR) with the Chronic Kidney Disease
in particular need of further study in the recent European Society 16
5
of Cardiology (ESC) HF guidelines. HFmrEF may be more similar
... ...
Epidemiology Collaboration (CKD-EPI) equation. CKD was defined
.
to HFpEF or to HFrEF, it may be a transition between the two, 2
as an eGFR ≤60 mL/min.1.73 m , in line with earlier studies of HF
...
or it may be a distinct syndrome. HFpEF may be a separate syn- 4
... ... ...

and CKD. Ejection fraction was obtained from the latest available
... ...
drome dominated by diastolic dysfunction, similar to HFmrEF and measurement and method according to local practice (in Sweden
HFrEF or merely a manifestation primarily of age and age-related
generally echocardiography with the Simpson method).
...
9 10
co-morbidities, obesity, and deconditioning.
... ... ...
, We defined HFpEF as left ventricular ejection fraction (LVEF) ≥50%,
... ..
The link between CKD and HFmrEF and HFpEF is poorly HFmrEF as LVEF 40– 49%, and HFrEF as LVEF <40%, according to
understood. There are no studies specifically comparing HFpEF, 5,17

contemporary recommendations.
... ...
HFmrEF and HFrEF with regard to CKD. Earlier reports did not
...
The study conforms to the declaration of Helsinki and was approved
differentiate between HFpEF and HFrEF,11 included highly selected
..
...
by the regional ethics review board in Linköping.

patients,12 examined only short-term prognosis,13 or CKD was
...
. . . . . . . . .. . . . . . . . .
examined only as part of a general co-morbidity burden. 14 Dependent variables and outcome
... ... ... ... ...
Thus, the aim was to perform the first large, generalizable In assessing the association between baseline variables and baseline
comprehensive comparison of CKD in HFpEF, HFmrEF, and CKD, the dependent variable was CKD. In assessing the association
between CKD and prognosis, the dependent outcome was death from
HFrEF with regard to prevalence, clinical correlates and long-term
...
any cause. Mortality data were obtained by running the registry against
prognostic role.
... ..... ..........
© 2017 The Authors
Methods
European Journal of Heart Failure © 2017 European Society of
Cardiology
Patients and baseline characteristics
15
The Swedish HF registry (SwedeHF) has been described previously. It
... .
is a web-based national quality register that has enrolled unselected HF

patients since 2000. The protocol, registration form and annual report
..
.. ... ... ...
are available online (http://www.SwedeHF.se).
Inclusion criterion is clinician-judged HF, and approximately 80
variables are recorded at discharge from hospital or during outpatient
visits to physician or healthcare team. Individual patient consent is
not required but patients are informed of entry into national quality
...
registers and allowed to opt out.

Descriptive continuous variables are presented as median and
interquartile range (IQR) and categorical variables are presented
as counts and proportions (%). Comparisons were made by
Pearson chi-square for proportions and Mann–Whitney test for
continuous variables. The index date was date of admission to
hospital or date of outpatient visit, respectively. Patients with
missing data for age or creatinine, creatinine measurement
methods not traceable to isotope dilution mass spectroscopy
standards, missing data of EF, repeat regis-trations or patients that
died during hospitalization were excluded. For remaining variables
missing data were handled by multiple imputation (n = 10) using
the same 28 variables as in the multivariable analyses below.
Associations between baseline variables and baseline CKD were

assessed with multivariable logistic regression using a total of 28 clini-cally
relevant variables: age, gender, civil status, care in cardiology ward,
hypertension, diabetes, smoking, ischaemic heart disease, atrial fib-rillation,
valvular heart disease, pulmonary disease, revascularization, hospitalization
at diagnosis, HF duration >6 months, New York Heart Association (NYHA)
class, haemoglobin, systolic blood pressure, heart rate, renin–angiotensin–
aldosterone system (RAAS) blockers, beta-blockers, aldosterone
antagonists, digoxin, statins, nitrates, oral
Figure 1 Patients included in the study from the Swedish Heart

Failure registry (SwedeHF). EF, ejection fraction; HFmrEF, heart
failure with mid-range ejection fraction; HFpEF, heart failure with
preserved ejection fraction; HFrEF, heart failure with reduced
ejection fraction.
the Swedish population registry, which includes the vital status of

all Swedish citizens and permanent residents.
Statistics
1608 I. Löfman et al.
Table 1 Baseline characteristics in absence and presence of chronic kidney disease
Variable HFpEF (n = 8875, 22.1%) HFmrEF (n = 8374, 20.8%) HFrEF (n = 22 981, 57.1%)
.............................. ................................ ...............................
% Missing eGFR ≥60 eGFR <60 eGFR ≥60 eGFR <60 eGFR ≥60 eGFR <60
pEF/mrEF/rEF (n = 3908, (n = 4967, (n = 4393, (n = 3981, (n = 12607, (n = 10 374,
44.0%) 56.0%) 52.5%) 47.5%) 54.9% 45.1%)
...........................................................................................................................................
Demographics
† * * *
Age 0 75 (65–82) 82 (77–86) 71 (62–79) 81 (75–85) 67 (59–76) 79 (72–84)
† * * *
Female 0 49.0% 59.0% 34.2% 45.5% 25.0% 33.6%
† * * *
Single 5, 4/4, 3/4, 5 46.2% 55.1% 37.4% 47.5% 37.0% 42.8%
* * *
Independent living 41, 7/39, 3/40, 0 94.4% 91.2% 96.8% 92.7% 96.5% 93.8%
† *** * *
Cardiac care 0/0, 1/ 51.5% 50.1% 55.7% 52.2% 59.7% 55.8%
† * * *
Specialist f-u 7/5, 2/4, 9 57.0% 42.8% 71.7% 52.5% 80.1% 61.4%
† * * *
HF unit f-u 6, 7/5, 1/5, 1 29.4% 22.8% 42.5% 30.2% 54.3% 40.1%
Risk factors
† * * *
Hypertension 2, 4/2, 4/3, 4 54.9% 62.7% 45.2% 57.7% 39.3% 50.8%
† * * *
Diabetes mellitus 1, 0/0, 7/0, 8 22.9% 28.7% 20.5% 29.3% 20.5% 28.5%
† * * *
Smoking 27, 8/22, 2/20, 1 14.2% 6.7% 15.2% 8.1% 20.0% 9.9%
* * *
Alcohol 54, 4/45, 5/41, 0 4.5% 2.5% 4.5% 2.0% 6.6% 2.6%
over-consumption
Heart disease
* * *
Previous MI 60, 8/62, 4/62, 4 23.4% 30.2% 30.5% 40.1% 30.3% 45.4%
† * * *
IHD 3, 9/3, 6/4, 9 33.9% 42.9% 45.7% 55.2% 43.2% 60.4%
† * * *
AF 0, 8/0, 8/0, 7 54.7% 62.8% 47.9% 60.0% 42.0% 51.5%
† * * *
VHD 2, 6/2, 6/2, 6 27.4% 30.0% 18.1% 25.6% 17.2% 24.5%
Comorbidity
* * *
Previous stroke 60, 3/61, 8/61, 6 12.1% 16.8% 10.7% 15.7% 9.2% 14.8%
† *** * ***
Pulmonary disease 2, 6/2, 5/2, 7 22.0% 22.5% 16.4% 19.2% 15.7% 16.4%
Previous procedures
† *** *** *
Revascularization 2, 2/1, 8/ 1, 7 18.8% 19.6% 28.9% 29.4% 25.9% 31.7%
*** ** **
Valve intervention 1, 5/1, 1/1, 2 7.5% 7.6% 6.2% 7.4% 4.8% 5.5%
*** *** *
CRT 1, 1/0, 9 /0, 9 0.5% 0.4% 1.0% 1.2% 3.1% 4.4%
Characterization of HF
* * *
Hospitalization at 0 70.2% 78.9% 51.4% 67.9% 50.9% 64.1%
†
inclusion
† * * *
HF > 6 months 0, 9/0, 5/0, 7 40.3% 54.9% 38.5% 55.8% 36.4% 57.9%
†
NYHA class
* * *
I 37, 1/28, 1/24, 1 21.6% 11.1% 20.8% 9.2% 11.7% 5.4%
* * *
II 45.5% 43.2% 54.1% 49.3% 51.0% 37.6%
* * *
III 30.4% 41.4% 23.6% 38.4% 34.4% 50.4%
* * *
IV 2.4% 4.2% 1.5% 3.1% 2.9% 6.6%
*
LVEF 30–39% 0 47.3% 49.1%
*
LVEF <30% 52.7% 50.9%
Variables are median (interquartile range) or per cent.
CRT, cardiac resynchronization therapy; eGFR, estimated glomerular filtration rate; f-u, follow-up; HF, heart failure; HFmrEF, heart failure with mid-range ejection fraction;
HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; IHD, ischaemic heart disease; LVEF, left ventricular ejection fraction;
MI, myocardial infarction; NYHA, New York Heart Association; VHD, valvular heart disease.
2 * ** ***
P-values comparing eGFR ≥60 vs. <60 mL/min.1.73 m within each ejection fraction group: P < 0.01, P < 0.05, not significant (P > 0.05).
† The 28 variables in the multiple imputation and multivariable analyses.
anticoagulants, antiplatelet treatment, specialist follow-up, and HF team

follow-up. Pre-selected variables of interest were illustrated in a Forest 100–139, and <100 mmHg, and haemoglobin into three categories:
.................
plot. When examining the association between continu-ous variables

and CKD, age was divided into three categories: <65, 65– 79, and ≥80 >150, 120–149, and <120 g/L.
years, heart rate into three categories: <70, 70–90, and ≥90 b.p.m.,
systolic blood pressure into three categories: >140,
Crude survival was assessed and illustrated with Kaplan–
Meier analyses.
Univariate and multivariate Cox proportional hazard regression

analysis was used to examine the association between CKD and
© 2017 The Authors

Table 2 Physical signs, laboratory results and medical treatment in absence and presence of chronic kidney disease
Variable HFpEF (n = 8875, 22.1%) HFmrEF (n = 8374, 20.8%) HFrEF (n = 22 981, 57.1%)
...................................... ................... .................. .........................................
% Missing eGFR ≥60 eGFR <60 eGFR ≥60 eGFR <60 eGFR ≥60 eGFR <60
pEF/mrEF/rEF (n = 3908) (n = 4967) (n = 4393) (n = 3981) (n = 12 607) (n = 10 374)
...............................................................................................................................................................
Physical status
† *** * ***
Heart rate 7, 1/6, 8/6, 0 72 (63– 82) 71 (63– 82) 70 ( 61–80) 72 (64– 84) 72 (64– 84) 72 (64– 82)
† *** *** ***

Systolic BP 1, 3/0, 9/1, 0 130 (120–145) 130 (120–150) 130 (115–140) 130 (115–144) 120 (110–140) 120 (110–140)
* * *
Diastolic BP 1, 4/1, 0/1, 1 73 (65– 80) 70 (60– 80) 75 (65– 80) 70 (60– 80) 75 (65– 80) 70 (60– 80)
*** * *
BMI 53, 8/51, 9/51, 7 27 (23– 31) 27(23– 31) 27(24– 30) 26(23– 30) 26 (23– 30) 25 (23– 29 )
ECG
* * *
Non-sinus rhythm 1, 3/1, 3/1, 0 47.2 % 57.2 % 42.3 % 55.3 % 38.0 % 49.4 %
* * *
Left branch block 17, 5/17, 9/16, 6 6.5% 8.9% 13.0% 14.6% 22.7% 26.8%
*** * *
QRS width, ms 30, 5/30, 7/30, 3 94 (86–106) 96 (86–112) 98 (88–114) 100 (88–122) 106 (94–130) 112 (96–140)
Laboratory tests
† * * *
Hb, g/L 0 131 (120–143) 123 (112–135) 136 (124–147) 127 (115–139) 139 (127–150) 130 (118–142)
* * *
Creatinine 0 75 (65– 86) 119 (101–147) 78 (68– 90) 122 (105–149) 81 (70– 92) 125 (109–153)
* * *
Potassium 42, 1/39, 3/39, 4 4.0 (3.8–4.3) 4.1 (3.8–4.4) 4.1 (3.8–4.4) 4.2 (3.9–4.5) 4.2 (3.9– 4.4) 4.2 (3.9– 4.5)
* * *
NT-proBNP 69, 5/70, 4/68, 4 1644 (738– 3160) 3014 (1413– 5903) 1574 (606– 3465) 3747 (1760– 7840) 2346 (1044– 4936) 5040 (2288–10890)
Medication
* * *
ACE-inhibitor 0, 8/0, 6/0, 5 57.3% 46.5% 71.7% 55.0% 78.7% 63.7%
* * *
>50% Target dose 49, 3/36, 7/28, 6 73.3% 68.1% 77.6% 71.1% 80.3% 72.3%
* ** *
ARB 2, 0/1, 7/1, 9 19.2% 22.3% 19.8% 22.9% 19.4% 23.8%
* * *
>50% Target dose 79, 3/79, 0/79, 0 55.6% 45.5% 60.2% 45.2% 59.4% 43.8%
† * * *
RAASB 1, 1/0, 7/0, 5 75.3% 67.4% 90.1% 76.5% 95.4% 85.1%
† * *** *
Beta-blockers 0, 7/0, 5/0, 4 78.1% 81.3% 85.9% 86.8% 91.8% 89.9%
*** *** *
>50% Target dose 21, 4/14, 5/9, 8 64.4% 63.6% 63.6% 64.7% 65.7% 62.7%
*** * ***
Aldosterone 0, 9/0, 7/0, 7 26.0% 27.6% 21.0% 26.1% 33.3% 32.4%
†
antagonists
† * *** *
Digitalis 0, 7/0, 6/0, 6 19.6% 16.6% 15.6% 15.8% 18.8% 15.6%
† *** *** *
Statins 0, 7/0, 4/0, 5 38.2% 38.6% 47.6% 46.4% 46.9% 48.7%
† * * *
Nitrates 0, 9/0, 8/0, 7 13.8% 23.0% 10.9% 23.3% 9.6% 22.4%
† *** *** ***
Anticoagulant 0, 8/0, 6/0, 6 38.8% 39.6% 37.7% 39.5% 40.0% 38.8%
† * *** *
Antiplatelet 0, 7/0, 6/0, 6 44.1% 48.5% 51.2% 52.9% 48.9% 55.1%
HFmrEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; eGFR, estimated glomerular filtration rate; BP, blood
pressure; BMI, body mass index; ECG, electrocardiogram; Hb, haemoglobin; NT-proBNP, N-terminal pro-brain natriuretic peptide; ACE, angiotensin-converting enzyme; ARB, angiotensin
II receptor blockers; RAASB, renin–angiotensin–aldosterone system blockers.
Variables are median (interquartile range) or per cent.
2 * ** ***
P-values comparing eGFR ≥60 vs. <60 mL/min.1.73 m within each ejection fraction group: P < 0.01, P < 0.05, not significant (P > 0.05).
†
The 28 variables in the multiple imputation and multivariable analyses.
mortality. Adjustments were made for the same 28 variables as above.
.. ..
but younger and less often female than HFpEF (Table 1
Analysis of interaction between CKD and HFpEF/HFmrEF/HFrEF was and the Supplementary material online, Table S1).
... ... ... ...

performed by creating an interaction term in a Cox regression analysis.
There was more hypertension, atrial fibrillation and valvular heart
Prognostic value of kidney function, regardless of chosen cut-off disease in HFpEF while there was more ischaemic heart dis-ease
value for eGFR, was assessed by area under the curve in receiver and revascularization in HFmrEF and HFrEF, all increasing with
worse kidney function. There were no differences in proportions of
operating characteristic (ROC) analyses.
diabetes between HFpEF, HFmrEF, and HFrEF, but higher pro-
portions in those with CKD. Patients with worse kidney function
. . . . . . . . . . . . . . . . . .. . . . . . . . .
Results more often had HF with longer duration and were in a more severe
NYHA class regardless of EF.
Patients and baselines characteristics
In HFpEF and HFmrEF patients had higher systolic blood pres-
From May 11, 2000 until October 3, 2013, a total of 88 317 reg-
sures and in HFpEF slightly higher body mass index, with no major
istrations occurred in SwedeHF. After excluding repeat registra- differences in the presence vs. absence of CKD (Table 2 and the
Supplementary material online, Table S2). It was found that HFpEF
tions and applying the exclusion criteria above, a total of 40 230
had lower haemoglobin level than HFmrEF and HFrEF and in all
unique patients were included. Of these, 8875 (22%) were classi- groups the haemoglobin level decreased with lower kidney
function. N-Terminal pro-brain natriuretic peptide (NT-proBNP)
fied as HFpEF, 8374 (21%) as HFmrEF, and 22 981 (57%) as HFrEF
... ... ... ... ...
level was lowest in HFpEF and HFmrEF and highest in HFrEF, and
(Figure 1). approximately the double in CKD vs. non-CKD, regardless
There was a higher prevalence of CKD in HFpEF than in HFmrEF
and HFrEF (56% vs. 48% and 45%, respectively, P < 0.001). Patients
with HFmrEF were older and more often female than HFrEF,
© 2017 The Authors

H ge, this is the first large, generalizable, long-term, comprehensive

F comparison of CKD in HFpEF, HFmrEF, and HFrEF
m
of EF. In all EF categories, CKD was associated with r
greater age, co-morbidity, and severity of HF. E
F
There was lower use of angiotensin-converting enzyme th
(ACE)-inhibitors and angiotensin receptor blockers (ARBs) in a
CKD and with progressive renal dysfunction, but for n
aldosterone antagonists this was true only at the lowest eGFR in
(Table 2 and the Supplementary material online, Table S2). H
F
p
E
Associations between covariates F
and chronic kidney disease p
at
ie
To elucidate the independent risk markers and potential risk nt
factors for CKD, the independent associations were assessed s
between important baseline covariates and CKD, separately in (
HFpEF, HFmrEF, and HFrEF (Figure 2). There were numerous Fi
baseline variables independently associated with CKD,
g
including greater age, female sex, hypertension, diabetes,
u
longer duration of HF, and NYHA class. Anaemia was strongly
r
associated with CKD, whereas ischaemic heart disease and
e
atrial fibrillation were not strongly associated with CKD after
4)
adjustments for covariates. Notably, the associations with CKD
.
changed somewhat after mul-tivariable adjustment, but were
similar regardless of EF category. As expected, prescription of
RAAS blockade was associated with lower odds of having CKD
while beta blockers were associated with higher odds (see the
Supplementary material online, Tables S3–S5). D
i
s
Associations between chronic c
kidney disease and mortality
u
Over a median (IQR) follow-up of 900 (369–1669) days, there were s
10 862 deaths overall. Within each EF group, patients with CKD
s
had a worse outcome both in the short and long term (Table 3,
Figure 3). In the crude survival analyses patients with HFpEF, i
HFmrEF, and HFrEF had similar poor prognosis in the presence of
CKD, whereas in the absence of CKD, HFpEF had higher 1-year,
o
5-year, overall, and long-term mortality compared with HFmrEF n
and HFrEF. Accordingly, in the unadjusted analysis, CKD was less
strongly associated with mortality in HFpEF than in HFmrEF and
HFrEF and remained less associated with mortality after multiple T
adjustments (P for interaction <0.001), although the effect of o
adjustment was greater in those with HFmrEF and HFrEF than for o
HFpEF (Table 4). In patients with CKD, there was a stronger
ur
association between renal function and mortality in patients with
k
HFmrEF and HFrEF (see the Supplementary material online,
n
Figure S1).
o
wl
In ROC analyses of 1-year mortality, the prognostic discrimina-
tion of kidney function, measured as eGFR as a continuous e
variable in area under the curve analysis, was larger in HFrEF and d
Figure 2 Multivariable logistic regression: association with
chronic kidney disease. CI, confidence interval; IHD,
ischaemic heart disease; Hb, haemoglobin; HF, heart failure;
HFmrEF, heart failure with mid-range ejection fraction;
HFpEF, heart failure with preserved ejection fraction; HFrEF,
heart failure with reduced ejection fraction; NYHA, New York
Heart Association; OR, odds ratio.
........................................................................................................................................................................
5
according to the new HF types in the recent ESC HF guidelines.
There were several important findings. The associations between
CKD and characteristics such as greater age, female sex, and
greater severity of HF were similar in the three groups. However,
HFpEF stood out as different compared with HFmrEF and HFrEF,
which were more similar. In HFpEF, CKD was more common but
less important, with a weaker association with mortality, less
modification of risk by conventional HF risk markers, and with a
less discriminatory power for mortality.
In the present study, more than 50% had HFrEF. The proportions of
HFpEF and HFmrEF were equally common, with the proportion of
HFpEF being slightly lower than that in earlier studies. 18,19 We found a
proportion of CKD in HFpEF of 56%, which was higher than
© 2017 The Authors

Table 3 Mortality in heart failure with preserved (HFpEF), mid-range (HFmrEF), and reduced ejection fraction
(HFrEF) according to absence or presence of chronic kidney disease
HFpEF (n = 8860) HFmrEF (n = 8350) HFrEF (n = 22 953)

............................... ................... ............ ................................
eGFR ≥60 eGFR <60 eGFR ≥60 eGFR <60 eGFR ≥60 eGFR <60
...........................................................................................................................................
* * *
1-year mortality 13.4% 22.6% 7.8% 22.4% 8.0% 23.0%
5-year mortality 41.8% 67.1% 32.0% 63.1% 31.1% 63.7%
Deaths/100 patient-years, n 2.79 4.41 2.23 4.79 2.04 4.49
eGFR, estimated glomerular filtration rate.
* 2
P < 0.001, comparing eGFR ≥60 vs. <60 mL/min.1.73 m within each ejection fraction group.
Figure 3 Kaplan–Meier curves for long-term mortality in heart failure with preserved (HFpEF), mid-range (HFmrEF), and reduced
ejection fraction (HFrEF). eGFR, estimated glomerular filtration rate.
in HFrEF and HFmrEF and higher than that seen previously, 14,20 and
..
diabetes, an important contributor to CKD, which has been
consistent with the unselective nature of SwedeHF compared with
... ... ... ...

observed in varying proportions in previous studies. 14,23
clinical trial databases. How-ever, this does not rule out the possibility that the
mechanisms by which diabetes may contribute to HF may
vary according to EF.
Our study differs from previous reports, in which the HFmrEF
has either been excluded or grouped with the HFpEF or HFrEF

When examining the associations between CKD and
6,14,21 .. different covariates in the three types of HF, we found almost
population. Instead, the present study provides a novel and similar associations between baseline characteristics and CKD
... ... ... ... ... ... ... ... ... .... .
in the three EF groups after multivariable adjustments. Age was

detailed description of the HFmrEF group, where many clinical
the most important variable associated with CKD even after
characteristics such as age, proportion of females, and hyperten- multiple adjustments; this is not unexpected as age is indeed a
component of the calculation of eGFR. Haemoglobin as part of
sion were on a continuum between HFpEF and HFrEF but certain
the cardiorenal syndrome showed an independent association
characteristics, such as ischaemic and valvular heart disease, were with CKD, as did diabetes and hypertension. A possible
explanation is that drivers of CKD are similar in HF regardless
distinctly more similar to HFrEF than to HFpEF.
of EF. However, the effect of CKD in the different EF groups
As seen in other studies, the HFpEF population was older, regarding severity and outcomes may still differ.
more often female, had more co-morbidities, more often included
a hospitalization, and more often were living alone— all signs
consistent with frailty, which may contribute to higher mortal-
ity in HFpEF than in HFmrEF and HFrEF among patients with-
out CKD.10,22 There were no differences in proportions of

...
© 2017 The Authors

Table 4 Association between chronic kidney disease and mortality according to ejection fraction category
Model HFpEF HFmrEF HFrEF

.......................... .......................... ...........................
HR 95% CI HR 95% CI HR 95% CI
...........................................................................................................................................
Crude 1.95 1.83–2.08 2.64 2.46–2.84 2.75 2.64–2.88
Adjusted age 1.40 1.31–1.50 1.72 1.60–1.86 1.80 1.72–1.89
Adjusted age and gender 1.41 1.32–1.56 1.73 1.61–1.87 1.82 1.74–1.90
*
Adjusted all baseline variables 1.32 1.24–1.42 1.51 1.40–1.63 1.49 1.42–1.56
CI, confidence interval; HFmrEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with
reduced ejection fraction; HR, hazard ratio.
P-value for all <0.001.
* Age, gender, civil status, cardiology ward, specialist follow-up, heart failure team follow-up, hypertension, diabetes, smoking, ischaemic heart disease, atrial fibrillation,
valvular heart disease, pulmonary disease, revascularization, hospitalization at diagnosis, heart failure duration >6 months, New York Heart Association class, haemoglobin, systolic
blood pressure, heart rate, renin–angiotensin–aldosterone system blockers, beta blockers, aldosterone antagonists, digoxin, statins, nitrates, oral anticoagulants, and antiplatelet
treatment.
Figure 4 Estimated glomerular filtration rate as predictor of 1-year mortality: receiver operating characteristic (ROC) curves and area
under the curve. HFmrEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF,
heart failure with reduced ejection fraction.
The literature concerning mortality in HFpEF and CKD is incon-

sistent. Chronic kidney disease was found to be a more power-ful The risk associated with CKD was lower in HFpEF in both
univariate and multivariate analyses but was reduced by less
......................................................
predictor of death in patients with HFpEF than in HFrEF in the
4 when adjusting for multiple covariates. Together, these findings
extensive meta-analysis of Damman et al. with over 80 000
suggest that while CKD is common in HFpEF, it represents one
patients and was thought to be caused by underlying disease such
of many co-morbidities and may have more of a bystander role
as hypertension and diabetes, associated with impaired GFR and
worse outcome. This was however contradicted by the Meta- than it does in HFmrEF or HFrEF, where it may be more
Analysis Global Group in Chronic Heart Failure (MAGGIC) meta- intricately tied to the HF syndrome itself and its severity.
analysis showing a lower mortality rate and lower association
between CKD and death in patients with HFpEF than in HFrEF, Although the present study improves the understanding of
4 24 25
which is in line with our results. , , CKD in different types of HF, we can only speculate about
underlying mechanisms. In HFrEF the cardiorenal syndrome
has been well described. The presence of CKD may capture
In the present study, CKD was strongly associated with mortality
patients with a more advanced HF stage. Chronic kidney
4
in all EF groups, in keeping with earlier studies. In the crude disease seems to be secondary to both backward and forward
analyses of patients with CKD, there were no differences in short- failure, sympathetic and neurohormonal activation, and
and long-term mortality between the three EF groups. In the 1
contributes to further cardiac deterioration.
absence of CKD, HFpEF was associated with considerably greater
mortality than HFmrEF or HFrEF. This implies similarities between
HFrEF and HFmrEF and a distinction vs. HFpEF. In HFpEF, the link appears less clear. Both CKD and HFpEF
may be unrelated reflections of the greater age and co-morbidity
burden or they may evolve independently of one another or
© 2017 The Authors

... ....
secondary to the same risk factors. Earlier studies have shown As a descriptive real-life study the present study was not designed
... ... ... ... ..

that HFpEF seems to be associated with endothelial dysfunction to draw direct conclusions about directions of associations and
and inflammation, and a new paradigm has been proposed for 2 , even
..
HFpEF where co-morbidity induces an inflammatory state with causality. We defined CKD as eGFR ≤60 mL/min.1.73 m
.
though the current actual definition of kidney disease also involves
...
microvascular dysfunction potentially leading to both cardiac and
–28 This may have led to some misclas-
..
32
renal fibrosis.26
...
measurement of albuminuria.
.. .
Increased central venous pressure has been found to be associ-
... ...
4
sification, but is in line with earlier studies of HF and CKD. All
ated with impaired renal function both in patients with reduced
... ... .
eGFR data were at baseline only and we did not have access to
and preserved EF.29 It has been proposed that HFpEF patients
... ... ...

longitudinal changes. Although SwedeHF is nationwide, coverage
are more susceptible to low blood pressure regarding renal func-
is incomplete and our cohort may not be completely generaliz-
... ... ... ... ... ...

tion, being more preload dependent and having more autonomic
able to the entire Swedish HF population or to other geographical
dysfunction with ventricular and arterial stiffness. 28 This may con-
...
settings. Some variables entering multivariable models had missing

tribute to the observed higher proportion of CKD in HFpEF in our
...
data, which was handled by multiple imputation. There may have

material.
... ... ...
been some misclassification of EF in the echocardiographic mea-

On the other hand, CKD may contribute to the development of
surements, as all EF data were baseline data, not capturing potential
HFpEF as greater age, urine albumin, cystatin C have been found
changes over time, and the EF measurements were not adjudicated.
... ...
to be strong risk factors for new-onset HFpEF30 and albuminuria
... ...
However, overall, the present study reflects prevalence and prog-

in combination with reduced eGFR is associated with both hyper-
nosis as defined in the current daily practice.
...
trophy and cardiac remodelling.26
... ... ...
... .... ........

Finally, the lower use of RAAS inhibitor therapy with declining Conclusion
renal function was not unexpected but raises several issues.
Chronic kidney disease was associated with similar covariates
Although trials have excluded and guidelines do not rec-
...
regardless of EF. Although CKD was more common in HFpEF than

.. ...
ommend the use of RAAS inhibitors in patients with eGFR © 2017 The Authors
25
European Journal of Heart Failure © 2017 European Society of
previous observational data suggest RAAS
<30 mL/min.1.73 m ,
Cardiology
.. ... .
inhibitor therapy may be associated with improved outcomes even
31
in severe renal failure, a question that is particularly relevant
... ... ... .... .
with the emergence of novel potassium binders.
Furthermore, the association between use of RAAS inhibitors
and outcomes in HFpEF, and in particular HFmrEF, continues to
be an important area of study, and the potential interactions with
CKD are particularly relevant for future trial design.

...... ...
Limitations
3. Ronco C, Haapio M, House AA, Anavekar N, Bellomo R. Cardiorenal
syndrome. J Am Coll Cardiol 2008;52:1527–1539.
in HFmrEF and HFrEF, it was less strongly associated with mortality and
4. Damman K, Valente MA, Voors AA, O’Connor CM, van Veldhuisen DJ, Hillege
had less prognostic discrimination in this subset of patients. HL. Renal impairment, worsening renal function, and outcome in patients with
heart failure: an updated meta-analysis. Eur Heart J 2014;35:455– 469.
5. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V,
González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoy-
Supplementary Information annopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka
F, Rutten FH, van der Meer P. 2016 ESC Guidelines for the diagnosis and treat-ment
of acute and chronic heart failure: the Task Force for the diagnosis and treatment of
acute and chronic heart failure of the European Society of Car-diology (ESC).
Developed with the special contribution of the Heart Failure Association (HFA) of the
Additional Supporting Information may be found in the online ESC. Eur J Heart Fail 2016;18:891– 975.
version of this article:
6. Hillege HL, Nitsch D, Pfeffer MA, Swedberg K, McMurray JJ, Yusuf S,
Granger CB, Michelson EL, Östergren J, Cornel JH, de Zeeuw D, Pocock S,
Figure S1. Association between renal function and mortality in van Veldhuisen D. Renal function as a predictor of outcome in a broad
spectrum of patients with heart failure. Circulation 2006;113:671– 678.
different EF groups.
7. Lam CS, Solomon SD. The middle child in heart failure: heart failure with
Table S1. Baseline characteristics in HFpEF, HFmrEF, and mid-range ejection fraction (40– 50%). Eur J Heart Fail 2014;16:1049–1055.
HFrEF and different eGFR strata.
Table S2. Physical signs, laboratory results and medical treatment in

different eGFR strata in HFpEF, HFmrEF, and HFrEF.
Table S3. Associations with CKD, adjusted logistic regression.
Acknowledgements
The authors thank the steering group of the Swedish Heart

Failure Registry and all the hospitals and outpatient clinics that
report to the registry.
Funding
This work was supported by the Swedish Foundation for Strategic

Research, the Swedish Heart and Lung Foundation, and the
Stock-holm County Council (ALF project).
Conflict of interest: U.D. reports grants from AstraZeneca and

consultancies/honorarias from Novartis. T.J. reports fees for lecturing
and consulting from Astra Zeneca, Aspen, and MSD. L.H.L. reports
grants from the Swedish Research Council Swedish Heart Lung
Foundation and Swedish Society of Medicine, and grants and personal
fees from AstraZeneca, Boston Scientific, Bayer, Novartis, and Bayer,
outside the submitted work. I.L and K.S. have no conflicts of interest to
declare.
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Review
published: 28 February 2017
doi: 10.3389/fimmu.2017.00191
A Potential Role of Salmonella
Infection in the Onset of
Inflammatory Bowel Diseases
Bárbara M. Schultz1, Carolina A. Paduro1, Geraldyne A. Salazar1, Francisco J. Salazar-

Echegarai1, Valentina P. Sebastián1, Claudia A. Riedel2, Alexis M. Kalergis1,3,4, Manuel
Alvarez-Lobos5* and Susan M. Bueno1,4*
1 Facultad de Ciencias Biológicas, Departamento de Genética Molecular y Microbiología, Millennium Institute on

Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile, 2 Facultad de Ciencias
Biológicas y Facultad de Medicina, Departamento de Ciencias Biológicas, Millennium Institute on Immunology and
Immunotherapy, Universidad Andrés Bello, Santiago, Chile, 3 Facultad de Medicina, Departamento de Endocrinología,
Pontificia Universidad Católica de Chile, Santiago, Chile, 4 INSERM, UMR 1064, Nantes, France, 5 Facultad de
Medicina, Departamento de Gastroenterología, Pontificia Universidad Católica de Chile, Santiago, Chile
Schultz BM, Paduro CA, Salazar GA, Salazar-Echegarai FJ, Sebastián VP, Riedel CA, Kalergis AM, Alvarez-Lobos M
and Bueno SM (2017) A Potential Role of Salmonella Infection in the Onset of Inflammatory Bowel Diseases. Front.
Immunol. 8:191.
doi: 10.3389/fimmu.2017.00191
Edited by:
Eric Cox,
Ghent University, Belgium
Reviewed by: Benjamin P.

Willing, University of
Alberta, Canada Atte Von
Wright,
University of Eastern Finland,

Finland *Correspondence:
Susan M. Bueno
sbueno@bio.puc.cl;
Manuel Alvarez-Lobos
manalvarez@gmail.co
m
Specialty section: This

article was submitted to
Mucosal Immunity, a
section of the journal
Frontiers in Immunology
Received: 15 October 2016
Accepted: 09 February 2017
Published: 28 February 2017
Citation:
influence or contribute to the onset or development of the disease in susceptible
individuals. The infection with pathogenic bacteria is a key factor that can influence the
Inflammatory bowel development and severity of this disease. Here, we present a comprehensive review of
disease (IBD) includes a studies performed in human and mice susceptible to IBD, which supports the notion that
set of pathologies that infection with bacterial pathogens, such as Salmonella, could promote the onset of IBD
result from a deregu-lated due to permanent changes in the intestinal microbiota, disruption of the epithelial barrier
immune response that and alterations of the intestinal immune response after infection.
may affect any portion of
the gastrointestinal tract. Keywords: inflammatory bowel disease, Crohn’s disease, ulcerative colitis, gut microbiota, Salmonella enterica
The most prevalent and serovar Typhimurium, innate immune response, virulence factors
defined forms of IBD are

Crohn’s disease and
ulcerative colitis. Although
the etiology of IBD is not
INTRODUCTION
well defined, it has been
suggested that
environmental and genetic Inflammatory bowel disease (IBD) is defined as a set of pathologies that exhibit a progressive and
factors contribute to chronic phenotype, where the intestinal immune response and the normal gut microbiota are altered
(1). IBD usually begins in adolescence and persists lifelong (2). The symptoms of these inflammatory
disease development and
disease are not only limited to the gastrointestinal level but also produces systemic complications such
that the interaction as fever, weight loss, delayed sexual maturation and growth, among others. Further, extraintes-tinal
between these two factors diseases can be associated with IBD, including arthritis (3). The most common clinical mani-festations
can trigger the pathology. of IBD are Crohn’s disease (CD) and ulcerative colitis (UC) (2). CD, a manifestation that affects
Diet, medication use, females in a greater proportion, is characterized by a chronic and transmural inflammation, specifically
at the colon and small intestine. However, inflammatory lesion during CD can be found at any section
vitamin D status, smoking,
of the gastrointestinal tract, from the mouth to the anus (4). These lesions can affect
and bacterial infections
have been proposed to
Frontiers in Immunology | www.frontiersin.org 1 February 2017 | Volume 8 | Article 191

Schultz et al. Salmonella and IBDs
all layers of the gastrointestinal tract, producing strictures and

fistulae (5, 6). CD mostly affects the young population, with a peak
of incidence in the early adulthood (between 20 and 30 years old).
UC, on the other hand, is a manifestation more common in males
and only affects the superficial layer of the colon, with a
continuous inflammation comprising from the rectus to vari-able
distances along the intestine (6, 7). The incidence of IBD is higher
in industrialized or westernized regions, such as the United States
and Northern and Western Europe, and it is mild in South America
and Africa (8). The same pattern is observed in urban and rural
areas, indicating that industrialization can be considered as an
etiological factor for major incidence of IBD (7, 8). Additional
factors, such as environmental and genetic factors, interact to
determine the onset and development of disease.
Different studies have shown the correlation between environ-

mental and genetic factors that could lead to a dysfunction of the
intestinal epithelial barrier, with a consequent deregulation in the
function of the mucosal immune cells. These alterations lead either
to an inappropriate recognition of the gut microbiota or an
increased susceptibility to infections (7, 9). Moreover,
environmental factors can differentially affect predisposition of
individuals, by increasing their susceptibility to develop IBD (10).
The increase in the incidence of IBD has been associated with
several factors common to modern lifestyle, such as use of
antibiotics, vaccines, contraceptives, vitamin D status, and better
hygiene. Further, changes associated with westernization, such as
high consumption of fats, refined sugar, and carbohydrates, have
also been implicated in the incidence increase for these diseases
during the last decades (11). According to previously observed
associations between the consumption of some food and incidence
of UC or CD, it is presumed that the diet could induce changes in
the microbiota composition and in the cellular adhesion to the
intestinal barrier (12), which could in turn lead the development of
IBD (11).
Inflammatory bowel disease is a disease highly influenced by

genetic factors. Several genetic mutations and polymorphism have
been described in both UC and CD (13–15). Interestingly, some of
the polymorphisms associated with IBD locate in genes encoding
proteins involved in bacteria recognition, degradation, or
translocation through the intestinal epithelial barrier. For instance,
it has been described that in both UC and CD patients there are
polymorphisms in genes associated with the Th1/Th17 pathway
[il23r (16), il12b (17), or stat3 (17) genes]; autophagy [atg16l1
(18), irmg (19), and nod2 (20)]; and epithelial barrier [jak2 (13)
and il-10 (14)]. These mutations affect the capacity of the innate
immune cells to handle intracellular bacteria due to an aberrant
autophagy process. These alterations result in a response unable to
control systemic bacteria spread, which predisposes the host to an
increased pathogen colonization and an enhanced susceptibility to
these diseases (21). Another gene involved in CD is nod2, which
encodes the nucleotide-binding oligomerization domain-containing
protein 2 (NOD2). This gene is in chromosome 16 and encodes an
intracellular receptor for the muramyl dipeptide (MDP), a
component of bacterial cell wall. When this gene is silenced, it is
observed that an aberrant IL-1β production occurs in response to
bacterial endotoxins, which leads to an impaired early immune
response (22, 23). Mutation
CONTRIBUTION OF THE INTESTINAL
EPITHELIAL BARRIER TO BACTERIAL
in nod2 also affects the function of Paneth cells, diminishing the
production of α-defensin, an antimicrobial peptide secreted by this INFECTIONS AND IBD DEVELOPMENT
type of cells (24, 25). Variants of this gene, combined with
polymorphisms in tlr9 or atg16l1, increase the risk of suffering
IBD (22). The atg16l1 gene encodes a key protein in the process of The intestinal epithelial barrier physically separates the intestinal
autophagy (9), which is required for a proper innate immune lumen from deeper layers, such as the lamina propria (29). It is
response against microorganisms. Mice ATG16L1HM, which carry organized in crypts and villi and composed of four types of
a disruption of the atg16l1 gene with a concomitant decreased specialized cells: absorptive enterocytes that have metabolic and
protein level, display abnormal Paneth cells function due to a digestive functions and can also secrete some antimicrobial pep-
defect of the granule exocytosis pathway. Such a phenotype can tides; goblet cells, specialized in mucus secretion; enteroendocrine
also be observed in CD patients. In consequence, the secretion of cells that secrete hormones; and Paneth cells that mostly secrete
lysozyme is altered, and the expression of genes involved in injury antimicrobial peptides into the crypts of the small intestine (Figure
response is increased (26). These data indicate that Paneth cells 1A) (29). M cells, which are specialized follicle-associated
have a unique sensitivity to autophagy gene disruption, which lead epithelial cells that cover Peyer’s patches, are found in the small
to endoplasmic reticulum stress in the intestinal epithelium. Thus, intestine. The function of these cells is sensing luminal content, a
the autophagy process could have a specific role in these cells, as it task required for the correct functioning of the epithelial barrier.
seen in CD patients (26–28). In another study, research-ers found Antigens and microbes captured by M cells are transported across
that patients with variants in nod2 and/or atg16l1 genes display an the epithelial barrier and presented to immune cells residing in the
increased secretion of TNF-α in response to bacterial translocation lamina propria, through a process denominated transcytosis, which
through the intestinal epithelial barrier, which is directly related to is essential for antigen-specific mucosal immune response (Figure
the aggravation of intestinal inflammation, disease activity, and 1A) (30).
relapsing episodes (22). Through genetic analyses, it was shown
that CD has more genetic components (such as loci associated with Through the intestinal barrier, there are several proteins that
susceptibility to the disease) than does UC (21). Therefore, a better monitor the environment of the intestinal lumen. Pattern-
knowledge of the genetic variables and their interaction with recognition receptors (PRRs), for instance, are proteins expressed
environmental factors will generate a breakthrough in by different type of innate immune cells located in the intestinal
pharmacogenomics, which could be used as a treatment for the tissue, such as dendritic cells, phagocytic macrophage and
disease, improving the tolerability and effectiveness of the
therapies used nowadays (21).

Figure 1 | Normal intestinal epithelium versus altered intestinal epithelium observed in inflammatory bowel disease (IBD). (A) The normal intestine presents a high
secretion of bactericidal molecules (defensins, REGIIIγ, and IgA) as mechanisms of defense against pathogenic bacteria. The commensal microbiota inhibits the access of
pathogens to the epithelial barrier by competing for nutrients, maintaining homeostasis of the epithelial barrier, and supporting the host immune response. The commensal
microbiota is composed of mainly Firmicutes and Bacteroidetes, and a lower percentage of Proteobacteria and Actinobacteria. They promote the secretion of mucus and
antimicrobial peptides [short-chain fatty acid (SCFA), H2S] and the activation of some pathway of immune system such as the activation of macrophages and dendritic cells
in lamina propria, and the production of cytokines such as IL-6, IL-23, and IL-12, which activates Th1 or Th17 cells to produce cytokines acting on intestinal epithelium. (B)
The intestine of IBD patient has a deregulated response to commensal microbiota by a decrease in the secretion of antimicrobial peptides such as α-defensins and
increase in REGIIIγ as compensatory effect; these effects have relation with defect in Paneth and goblet cells. IBD patients showed lower Firmicutes and Bacteroidetes but
have increased amounts of Proteobacterias resulting in a decrease production of SCFA, mucus, and increased inflammation. The epithelium produces an abnormal
amount of IgG against commensal microbiota instead IgA. Macrophages produce higher amounts of cytokines that overstimulate Th1 or Th17 cells, which secrete pro-
inflammatory cytokines to epithelium.
negative and Gram-positive bacteria (35, 38). Among the NLRs,

NOD1 and NOD2 are the most studied. Both recognize products
released by division of intracellular bacteria and, after NOD2 is
activated, NF-κB translocates to the nucleus and allows the pro-
granulocytes, cytotoxic natural killer, and γδ-T cells; as well as duction of IL-6, IL-1β, and TNF-α, to trigger a pro-inflammatory
intestinal epithelial cells. PRRs sense pathogens through pathogen- response (39).
associated molecular patterns (PAMPs), such as LPS or flagellin
(31, 32). PRRs also have a role in the regulation of intestinal
M cells have another type of receptor, the glycoprotein-2
epithelial barrier, repair, and immune homeostasis (33, 34). The
PRRs include different type of members: toll-like recep-tors receptor (GP2), which is found in the apical side of epithelial
(TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), barrier and serves as transcytosis receptor for many antigens
and C-type lectin receptors (35, 36). RLRs and C-type lectin
receptors are mainly involved in viral and fungal recogni-tion,
respectively (35). TLRs are present in the surface of epithelial cells
and endosomes, and even some can be found inside Paneth cells or
enteroendocrine cell (35). TLRs are distributed in differ-ent
portions of the intestine and differentially expressed on the apical
or basolateral side of the cell. Then, the same PRR may respond
differentially depending on its localization. For instance, TLR5
only produces an inflammatory response if it binds flagellin in the
basolateral surface of the epithelial barrier, which involves the
transcription of pro-inflammatory cytokines (37). Other proteins
involved in pathogen recognition at the intestine are NLRs, which
are found in the cytosol of macrophages, dendritic cells, and Paneth
cells. These intracellular proteins sense PAMPs as well as
endogenous molecules released from damaged cells, called
damage-associated molecular patterns. NLRs can sense a
distinctive substructure from peptidoglycan of mostly all Gram-
are Bacteroidetes (Gram-negative) and Firmicutes (Gram-positive)
(40). It has been reported that microbial communities may change
due to age, nutrition, inflammatory processes, and gastrointestinal
disease (Figure 1A) (41), and it has been dem-onstrated that the
presence of commensal microbiota induces a basal expression of
derived from commensal and pathogenic bacteria. This endo- certain TLRs (such as TLR2 and TLR5), as compared to the basal
cytic receptor recognizes FimH, a component of type I pilus of levels of expression observed in specific-pathogen free mice and
diverse enterobacteria, such as Escherichia coli and Salmonella germ free mice (42). The same report shows that microbiota is
Typhimurium. GP2 interacts with bacterial pilus proteins, essential to trigger a proper inflam-matory response to infection by
allow-ing the capture of the bacterium by the cell and its some pathogenic bacteria ( 42). Thus, a complex interplay between
transport across the barrier to the Peyer’s patches and other gut-
the host immune system and the microbiota is required for gut
associated lymphoid tissues (29, 30).
microbiota homeostasis. For instance, the production of IL-6 and
TNF-α is triggered by com-mensal microbiota, and a proper
Another important component of the intestinal barrier is a wide functioning of TLR is required for protection against injuries of the
assortment of resident microbial communities that prevent intestinal epithelium. Thus, it is possible that the use of antibiotics
infection by competing with pathogenic bacteria. For example, in pharmacological dose could impair the production of these
commensal bacteria produce secondary metabolites that spe- cytokines due to a reduc-tion of commensal microbiota, which in
cifically inhibit members of the same or similar species able to turn might result in a reduced tissue repair ability (33).
cause infection. It has been shown that there are two bacterial phyla
that predominantly reside in the gut of healthy individuals; these

central role in the pathophysi-ology of the disease (50–52).

Although the blockage of these pathways did not improve the
histopathological score, it does
A defect in the functioning of any of the epithelial barrier
components mentioned above leads to an aberrant
inflammatory response and promotes susceptibility to some
diseases, such as IBD. In this case, it is known that defects in
the response of goblet and/or Paneth cells generate a type of
colitis or a spontaneous inflammation that resembles CD (29).
Further, the dual role of TLRs could be also an important factor
in the development of the disease (33, 42, 43).
DEFECTS IN THE IMMUNE RESPONSE TO

BACTERIAL PATHOGENS AND
MICROBIOTA DESCRIBED IN IBD
PATIENTS
As discussed above, the gut is constantly exposed to

commensal microbiota and foreign microorganisms introduced
by food consumption. The immune system helps to keep the
correct homeostasis between the immunosuppressive response
—which prevents overreaction to harmless antigens—and the
protec-tive response against pathogens (44). Intestinal tissue is
highly deteriorated in IBD patients, especially in CD patients,
due to an uncontrolled reaction of the immune system against
bacterial antigens (44, 45). Thus, the epithelium is highly
affected, and a pro-inflammatory response results in a loss of
tolerance to the normal microbiota (Figure 1B) (45).
Several alterations in mechanisms of epithelial barrier protec-

tion are related to the pathology of patients with IBD, because a
barrier dysfunction leads to impaired immune responsiveness, as in
this disease. One of them is, for example, the secretion of mucus by
goblet cells. IBD patients have decreased production and secretion
of mucin-2, the main component of the mucus, which is related to
the development of inflammation (46). This leads to a decreased
protection of the epithelial barrier and a greater number of bacteria
that are in direct contact with the epithelium (46, 47). Accordingly,
mice lacking the gene encoding Muc2 (Muc2 −/−) have increased gut
inflammation and weight loss, and this deficiency could contribute
to the onset and per-petuation of the colitis. Beside this, it is
important to mention that the microbiota has an important role in
regulating the secretion of colonic mucus (46, 48).
The process of epithelial regeneration after an injury is also

affected in IBD patients. Epithelial repair processes are divided in
two phases: the first one involves the re-distribution of the existing
cells, a process that is regulated by TGF-β. In the second phase,
cell proliferation is regulated by cytokines such as IL-6, secreted
by pro- inflammatory lymphocytes (27). TGF- β levels are
increased in active UC and CD patients, relative to control patients,
due to a constant inflammatory process and injury of the epithelial
barrier that must be repaired (49). IL-6 is induced early after injury,
allowing proliferation of intestinal epithelial cells that is needed for
a proper healing of the epithelium but also has functionality in
tumorigenesis and chronic inflam-mation. These functions may be
related to the development of cancer in IBD patient, having a
the disease (60). For example, CD patients have antibodies against
Saccharomyces cerevisiae (ASCA), E. coli, Pseudomonas
fluorescens, and flagellin (61), which are directly related to the
aggravation of the disease. Overreaction to these bacterial antigens
improve disease activity score, and it may have a therapeutic generates additional clinical manifestations, such as stenosis and
potential (53). internal perforations.
As previously discussed, the epithelial barrier must be

functional and not allow the entry of pathogens to the inner layers.
If the tight junctions are altered, the permeability of the barrier EFFECT OF ANTIBIOTIC TREATMENT
could increase and, along with this, there will be a greater IN IBD PATIENTS
paracellular flow of microorganisms, promoting the infection of the
lamina propria with pathogenic and/or opportunistic bacteria (54).
It has been described that both TNF-α and IFN-γ can modify these Inflammatory bowel disease is characterized by an augmented
junction structures, and it is known that IBD patients have an bacterial density at the mucosal level (62, 63), as well a dimin-
elevated production of TNF-α, which could be mediating the ished number of anti-inflammatory commensal bacteria, such as
increased permeability due to the loss of tight junctions structure the Gram-positives Firmicutes and Actinobacteria (56, 64). As a
(54). However, it is not well understood if this dysfunction is a consequence of this dysbiosis (dysregulation of commensal
consequence of increased inflammation during an active disease or microbiota), an increased number of potentially harmful bacteria
if it is the cause of IBD development, because some susceptible (such as Enterobacteriaceae) can occur, producing inflammation
patients without symptoms or those in remission also show altered (65). For these reasons, maintaining a proper ratio of these popu-
intestinal permeability (55). In normal conditions, the intestine is lations is highly relevant, because they constitute a barrier against
the major antibody producer tissue of the body, and the intestinal pathogenic bacteria (56). In support of this idea, studies have
mucous membrane contains more than 80% of the activated B cells shown that UC patients, even in remission, have dysbiosis when
(56). IBD patients have a dysfunction in the B cell response, which compared to controls, with increased numbers of opportunistic
involves an abnormal mucosal secretion of IgG antibodies against pathogens such as Campylobacter spp. and Helicobacter spp. (66,
commensal bacteria instead of the physiological secretion of IgA 67). Further, these patients show a reduction in the number of the
(Figure 1B) (57, 58). This overproduction causes an exacerbated cluster related to the metabolism of short-chain fatty acids
pro-inflammatory response and injury in the epithelium, which is (SCFAs), which generates less anti-inflammatory environment in
not observed in healthy individuals and may be relevant in the their guts (66). For these reasons, the use of antibiotic in IBD
development of the disease (59). Further, IBD patients also present patients to treat septic complication, such as abscesses and
antibodies to self-antigens or cross-reactivity against several
bacterial and fun-gal antigens, which often precedes the onset of

different routes (83, 84). The main route is through the activation
of virulence factors encoded in SPI-1. A second route of inva-sion
requires the rupture of tight junctions of the epithelial cells, which
changes the basal permeability of the intestinal barrier (85).
wound infection, is still conflicting because it decreases the
number of intestinal bacteria and alters the normal composition Finally, there is another entry through CX3CR1+ DCs (86)
of the microbiota (68). Moreover, treatment with antibiotics
increases the susceptibility of the patient to acquire an infection
by Clostridium difficile (68, 69).
Along the same line, some studies have shown that antibiotic
therapy is functional in UC and in CD, and the therapy works
better if given orally. Two meta-analysis supports the role of the
antibiotics in induction of the remission of IBD (70), specifi-cally
UC (71). This observation agrees with a study performed in some
pediatric patients with severe refractory UC, where the children
receive a triple therapy for 2–3 weeks with amoxicillin,
metronidazole, and doxycycline in children over 7 years of age.
This study shows that the treatment induced remission in 47% of
the patients and the effects observed depend on the physiological
characteristics of the patients and the current treatment used to
ameliorate the symptoms (69). A systematic review shows that the
induction of remission can occur in both CD and UC patients, but
that is still not sufficient information to recommend a type or a
cocktail of antibiotic to treat effectively the disease (72). In
summary, most of the processes described above, which can pro-
mote the onset and severity of IBD, are related to proper bacterial
location and clearance in the intestine. In the next section, we will
discuss how pathogenic bacterial infection could trigger IBD in
susceptible individuals.
Salmonella enterica INFECTION AND IBD
Many pathogenic microorganisms have been implicated in the

exacerbation or development of IBD (73): Campylobacter (1),
E. coli (74), Helicobacter pylori (75), Mycobacterium avium
subspe-cies paratuberculosis (76), and C. difficile (77). We will
focus on S. enterica serovar Typhimurium (1).
Salmonella enterica serovar Typhimurium (S.

Typhimurium) is a facultative, Gram-negative and intracellular
bacterium, which infects several host including humans (78). S.
Typhimurium can cause a severe inflammation of the intestinal
mucosal epithelium, resulting in humans, gastroenteritis, and in
mice, typhoid-like systemic illness (78). As every pathogen, S.
Typhimurium has several virulence genes, located in at least
five Salmonella pathogenicity islands (SPIs), which are genetic
elements within the Salmonella chromosome that was acquired
probably by hori-zontal gene transfer (79). The most important
and more studied SPIs are SPI-1 and SPI-2. Both SPIs encode
type III secretion systems (T3SS). These are complex
machineries formed by more than 20 proteins that allow
contact-dependent translocation of a set of different effector
proteins into the eukaryotic cytoplasm (80, 81). SPI-1 allows
Salmonella to invade epithelial cells, while SPI-2 allows the
survival and replication inside phagocytic cells (79, 82).
The first step in S. Typhimurium infection is to cross the intes-

tinal epithelial barrier, which can be accomplished through four
suppresses the apoptosis process during early steps of the
infectious process (92). All these mechanisms together allow S.
Typhimurium to produce inflammation of the intestine, without
destroying the epithelium.
interleaved in the epithelial barrier, reaching the bloodstream to
spread to extraintestinal sites, through the transport in CD18 + Toll-like receptors and NLRs recognize various compounds of
phagocytes (87). S. Typhimurium, activating pathways associated with a pro-
inflammatory response such as pyroptosis, which is a cell death
The second step in the cycle of infection of S. Typhimurium response that involves the production of caspase-1, required for the
is the expression of T3SS-2 inside immune cells, such as mac- secretion of mature IL-1β and IL-18 by macrophages (93, 94). For
rophages and DCs of the Peyer’s patches and lamina propria example, flagellin is recognized by TLR5 in the basolateral surface
(88), in which this bacterium can survive and replicate within a (30, 32, 37), which actively promotes the production of pro-
specific compartment known as Salmonella-containing vacuole inflammatory cytokines, such as IL-6 (95) and IL-8 (96), through
the activation of the transcription factor NF-κB and MAP kinases,
(SCV), which avoids lysosomal degradation and antigen
followed by the recruitment of inflammatory cells and the
presentation (83, 84). This initial invasion of the Peyer’s
activation of the adaptive immune response. Although immune
patches leads to an inflammatory response with recruitment of
cells rapidly clear bacteria, an important fraction disseminates to
immune cells, mainly neutrophils, which should prevent
deeper organs using phagocytic cells as a “Trojan horse.” Using
bacterial dissemination (Figure 2D).
this mechanism, S. Typhimurium can migrate from the site of
infection to the lymph nodes and activate T cells (97). In addi-tion,
S. Typhimurium can induce the production of caspase-1 via Nlrc4
IMMUNE RESPONSE AGAINST Salmonella (a type of NLR) through the recognition of flagellin, which enters
through the T3SS-1 to the cytosol of phagocytic cells. This
cytosolic response is independent of the one generated by TLR5
Commensal microbiota, mucus layers, antimicrobial peptides, and (extracellular) (36). In this way, S. Typhimurium uses this defense
tight junctions work together to maintain the integrity of the mechanism (production of inflammasome and pyrop-tosis process)
epithelial cellular barrier and prevent infection of pathogenic bac- to spread to other immune cells and disseminate systemically from
teria (89). Despite all these defense mechanisms, S. Typhimurium the gastrointestinal tract (93).
can modify tight junctions to increase the permeability of the
barrier, which allows its translocation through the epithelial cell During an infection with S. Typhimurium, the response of
monolayer, due to the secretion of a protein-denominated AvrA NOD1 or NOD2 occurs through the activation of the transcrip-
through the T3SS-1 (85). This protein impaired the activation of
tion factor NF-κB, which has an important role in the regulation
pro-inflammatory cytokine, such as IL-6 (90) and can affect
cellular proliferation activating the β-catenin pathway (91). Beside
this, AvrA can modulate the c-Jun N-terminal kinase, which

Figure 2 | Effect of Salmonella infection in inflammatory bowel disease (IBD) patients. In genetically susceptible to IBD patients, many parameters are
disrupted. (A) Paneth cells have an impaired secretion of antimicrobial peptides showing a decrease in the amounts of α-defensins, as well as increased
amounts of REGIIIγ, which is associated with impaired protection against pathogens. (B) Plasma cells have a polarized antibodies’ secretion to the production
of IgG antibodies targeting the individual’s own microbiota. Beside this, the proportions of commensal microorganisms present are unbalanced related to a
healthy host. Due to this imbalance, there is a decrease production of short-chain fatty acid (SCFA), which generates an increase in inflammation. Taken
together, these effects generate an environment more vulnerable to further infection. Furthermore, (C) S. Typhimurium recruits neutrophils to the lumen, which
generates ROS, producing tetrathionate in the intestinal lumen; this compound is used by Salmonella as electron acceptor, which gives advantage to S.
Typhimurium over the microbiota. (D) Salmonella infection is produced by the entry through DCs interspersed in the epithelial barrier or M cells that recognize it
through glycoprotein-2, accessing to the Peyer’s patches. (E) Salmonella can also get into the epithelial cells forming membrane ruffling or through disruptions
of tight junctions caused by itself and in this case especially in inflamed epithelium of IBD patients. (F) In the basolateral side, Salmonella can be recognized by
TLR5 stimulating an increased production of NF-κβ, which correlates with an enhanced recruitment of neutrophils, finally once within the epithelial cells,
Salmonella blocks the autophagosome pathway avoiding its own degradation.
of cytokine production. Thereby, it modulates the

transmigration of neutrophils to the source of infection and thus (Figure 2B). However, sometimes the immune response is
the intensity of the inflammation (Figure 2F). The activation of altered and generates an overreaction against its own
another signaling cascade via NOD2, triggered also by MDP, components, as in the case of IBD.
has a direct relation with the activation of the inflammasome
NLRP3 through NF-κB, caspase-1, and the consequent
secretion of IL-1β and IL-18 (98, 99). The correct function of
these receptors is important, because through its activation they Salmonella INTERACTION WITH
interact directly with the ATG16L1 protein and lead to the
MICROBIOTA
proper initiation of the autophagy process (99, 100).
All these effects produce an increase in inflammation after Commensal microbiota is mostly fermentative and produces at
bacterial infection because of the structure loss of the intestinal least three SCFAs, which are mainly acetate, propionate, and
mucosa, producing diarrhea with concomitant loss of liquid and butyrate (101). The concentration and distribution of these
electrolytes (97). This response against foreign microorgan- compounds vary along the gut and exert different effects on
isms must be controlled to reduce tissue damage or to prevent a colonization of pathogenic bacteria, such as Salmonella. In the
systemic infection, as it could be the case of S. Typhimurium ileum, there are higher concentrations of acetate, which induce
the expression of genes within SPI-1, allowing the invasion of
the ileum (101). Moreover, propionate and butyrate are present

The permeability of the epithelium in IBD patients is altered

and allows increased transcytosis of commensal and/or patho-
genic bacteria, which could generate an inflammatory response.
in higher amounts in colon and cecum (102) playing an antimi- When an infection with an invasive bacterial pathogen (such as
crobial effect, diminishing the expression of the same invasion
genes (101–103). Therefore, SCFAs produced by the
microbiota influence S. Typhimurium’s “choice” of the site of
colonization, and given that any change in the composition of
the microbiota will vary the proportion of these compounds,
they could allow for a different disease phenotype.
S. Typhimurium infection produces the transmigration of

neutrophils, which oxidize the endogen sulfur compound thio-
sulfate ( S2 O23− ) in the intestinal lumen, generating tetrathionate
( S4 O26− ) (Figure 2C) (104, 105). This product is an electron
acceptor for S. Typhimurium energetic processes and allows the
utilization of ethanolamine as a nutrient by the bacterium. This is a
competitive advantage over the fermentative bacteria from the
microbiota, which are unable to use this product, so
JJ Typhimurium will overgrow and disseminate (41, 105, 106).

Beside this, neutrophils induce the change of microbiota during
an infection with S. Typhimurium secreting a serine protease
(elastase), which has a direct effect to the microbiota (107).
This way, S. Typhimurium used both the inflammation and the
secretion of elastase to create a more favorable environment for
its own colonization. S. Typhimurium can take advantage of the
inflammatory response and promote its own growth and
dissemination into host tissues. Moreover, this pathogen could
play an important role in changing the microbiota composition
in genetic susceptible individuals or patients with a chronic
inflammation, such as IBD, due to mainly the dysbiosis in these
patients (41, 108).
S. Typhimurium INFECTION:
PREVIOUS OR AFTER IBD ONSET?
In this section, we will discuss some factors that could relate

the intestinal inflammation that occurs in IBD and the intestinal
infection caused by S. Typhimurium (Figure 2). A previous
study suggests a connection between S. Typhimurium infection
and IBD development (1). Furthermore, another study describes
the presence of Salmonella and other enteropathogen toxins in
the serum of IBD patients, which correlates to disease
progression (109). However, a following study in Danish
population sug-gested that increased detection of Salmonella
and Campylobacter in stools of IBD patients is due to detection
bias during the first year of infection (110). Although no
association of exposure to S. enterica in CD patients was
observed in a study made in another cohort of patient, a relation
between CD, cigarette smoking, and anti-Salmonella antibodies
in serum was observed (111). However, some studies suggest
that during the course of IBD, due to the dysbiosis of the
disease itself, the chances of an infection by enteropathogens
are higher (108, 112). Other studies showing positive results
with antibiotics treatment of IBD suggest the possibility of a
pathogenic agent as the causative agent of the disease (72).
these impaired processes are being observed in the ileum of
affected IBD patients and are more pronounced in individuals that
also carry mutations in the nod2 gene. However, these defects per
se are not translated in increased inflammation of the intes-tine,
S. Typhimurium) occurs, it generates the recognition by basolateral which suggests that an additional trigger (such as bacterial
TLR5 (Figures 2E,F), which initiates an inflammatory immune infection) may promote IBD in these susceptible patients (116,
response (37). It has been shown that the signaling through TLR5 117). A recent study has described that the polymorphism T300A
after flagellin recognition in a murine model of chemical-induced in the gene atg16l1 results in a defective production of C-type
colitis generates an increase in the secretion of pro-inflammatory lectin domain family 12 member A (CLEC12A) in CD patients, a
cytokines (32, 96) such as IL-8, which recruits neutrophils to the protein potentially involved in antibacterial autophagy (118). This
site of infection (113) and aggravates the clinical symptoms, study shows that absence of CLEC12A prevents S. Typhimurium
producing severe histopathological damage in the colonic mucosa clearance by HeLa cells and that mice lacking CLEC12A are more
(32). Therefore, IBD patients can be more susceptible to an susceptible to suffer a more severe infection (118). As mentioned
infection with a pathogen as S. Typhimurium, which could trigger above, mutations in the atg16l1 gene also alter the function of
the onset or aggravate the course of the disease, leading to a Paneth cells due to changes in the granule exocytosis pathway (26).
relapse. Additionally, S. Typhimurium synthesizes FimH, a protein In the same context, S. Typhimurium diminishes the granules
that binds to M cells by interacting with GP2. GP2 has an epitope production and the secretion of lysozymes by Paneth cells, through
recognized by “anti-pancreatic” antibodies found in CD patients the activation of p38/MAPK in the small intestine (117). This
(114), which could be a consequence of infection with this could be a survival mechanism of the bacterium and may be
pathogen or could involve the need for the combination between required by the subsequent infection process. Beside this, the
the receptor and FimH to produce antibodies. infection activates a differentiation program that results in
hyperplasia of Paneth cells in crypts, which could give as a result
an acute inflammatory response and have some effect in the
A deregulation of the secretory function of Paneth cells has
intestinal stem cells, due to an accelerated process of proliferation
been observed in IBD patients. For instance, CD patients have
(119). Further, S. Typhimurium generates hyperplasia of Paneth
diminished production of α-defensins at both mRNA and protein
cells through the activation of the Wnt pathway, but IBD patients
levels. Further, IBD patients have also an augmented secretion of
have deficiencies in different factors (such as Tcf4, for example) of
Reg-lectin family members, such as RegIIIγ, which has a
the same pathway, which is related to decrease the secretion of α-
compensatory effect in the decrease in α-defensins (Figure 2A).
defensin (120) (Figure 2A). The combination of virulence factors
This phenomenon is related to the increased adherence of the
displayed by S. Typhimurium and the genetic alterations
commensal microbiota to the enteric mucosa and an augmented
penetration of the commensal bacteria to the mesenteric lymph
nodes, which generates an inflammatory environment (115). All

These proteins are required for the correct function of NOD2 and
antigen presentation (125). Mutation in this gene generates
of the host that prevent correct bacterial clearance suggests that an

infection with S. Typhimurium in a susceptible host could gen-
erate changes in the proliferation and differentiation of Paneth
cells, which in patients suffering IBD will exacerbate the defect
produced by the mutation in some of the genes related to this
pathology, which finally will modify the lysozyme secretion, with
a consequent alteration in microbiota. All these changes generate a
new or different niche to the infection and finally the onset of the
disease with possible different phenotypes.
Other important factor related to IBD and S. Typhimurium

infection is the formation of autophagosomes. S. Typhimurium
survives inside the SCV without being recognized by the host cell.
However, if this compartment is damaged, ubiquitination can
modify the bacterium, leading to its autophagy encapsu-lation.
Despite this, Ssel, a soluble protein secreted by T3SS, actively
deubiquitinates the bacterium to prevent formation of the
autophagosome (121). In this context, the intestinal epithe-lium
responds to a S. Typhimurium infection with increased secretion of
factors related to the autophagosome formation (121) . Therefore,
the activation of this pathway is one of the main processes required
for resolution of the infection caused by this intracellular
bacterium. In IBD patients, there are three genes related to the
autophagosome process that are affected: irgm, nod2, and atg16l1,
each associated with different grades of susceptibility to suffer
IBD, which implies a defect in antigen uptake and its processing,
the interaction between dendritic cells and intestinal epithelial cell
(45), and the regulation of PRRs and inflammasome activation.
These genes encode proteins that are important to contain the
infection caused by
* Typhimurium (122).
Mutations in the atg16l1 gene generate defects in the formation

of autophagosomes, which implies that lower numbers of bacteria
will be captured and so less efficient bacterial clearance will occur
(121, 123). Beside this, patients with CD that carries an atg16l1
mutation (45) have an impaired degradation of S. Typhimurium,
making the host more susceptible to the infection. NOD2 is
required for the formation and activation of the phagosome and for
the recruitment of ATG16L1 to the site of entry of the bacterium,
therefore mutations in this gene generate lower levels of autophagy
and an impaired bacterial clearance (100). Mutation in the atg16l1
gene impaired the correct antibacterial function of NOD2 in
epithelial cells of the colon, and mutation in nod2 generates an
impaired signaling and bacterial killing, but this mutation only
partially affects the autophagy process (124). So, in this case, an
infection by S. Typhimurium in a susceptible host could be more
severe, as proper function of the above mentioned proteins is
required for the correct bacterial clearance and for the control of
dissemination of S. Typhimurium to extraintestinal sites, and this is
not necessarily related to the anticipated develop-ment of the
disease, but it is possible that all these factors could allow the
bacteria to survive longer inside the cells and generate an
inflammatory atmosphere that promotes the onset of IBD.
Some studies have demonstrated that MDP induces autophagy

in dendritic cells, a process that needs correct NOD2 signaling,
which in turn requires mainly the proper function of ATG16L1.
consequence, generate an abnormal inflammatory environ-ment.
All this, combined with a genetic susceptibility, will impair the
recognition of pathogens, the autophagy, tissue repair, and bacterial
clearance, generating an inflammatory condition at the intestinal
a malfunction in the autophagy process in dendritic cells, which epithelium.
indicates an aberrant bacterial trafficking and failure to produce
antigen presentation on MHC-II molecules, which in turns
promote the generation of antigen-specific, effector CD4 + T CONCLUDING REMARKS
cells (125). All these defects may allow bacteria to survive
longer inside dendritic cells, avoiding lysosomal degradation
for extended time (126, 127) and to provide a mechanism for
In this review, we discussed several microbial, cellular, and
the persistence of the pathogen and in consequence the
genetic alterations described so far in IBD patients, and related
persistent inflammation. Beside this, it has been reported that S.
these defects with the infection caused by S. Typhimurium. It is
Typhimurium employs dendritic cells expressing CCR7 as a
possible that S. Typhimurium infection could trigger chronic
pathway to migrate from the intestine to MLNs (127).
inflammation in individual carrying one or more of the defects
associated with IBD, given the inability of these patients to
The above background suggests that during an infection with S. prop-erly clear bacteria in the intestine. Moreover, S.
Typhimurium, the bacterial virulence factors and the defec-tive Typhimurium has an important arsenal of virulence factors to
processes in susceptible individuals, such as those described in IBD invade host cells in the intestinal epithelium and lamina propria
patients, could generate a persistence of the bacteria in dendritic that the normal microbiota is not able to reach. Additionally, it
cells, which would generate a continuous secretion of pro- is known that this bacterium can cause persistent infection in
inflammatory cytokines and an environment of inflam-mation, human and in mice, suggesting that in patients displaying one
which means that an infection with S. Typhimurium in these or more genetic defects that predispose to IBD development; it
patients could have a double effect, being more permissive to the is possible that they are much more susceptible to be infected
infection caused by this intracellular bacteria. Because of this, we by S. Typhimurium and cause a persistent infection. Permanent
propose that an infection with S. Typhimurium could anticipate the infection of cell with S. Typhimurium could promote secretion
onset of the disease, due to the atmosphere of inflammation that it of pro-inflammatory cytokines by infected cells, generating an
generates. Furthermore, the infection with S. Typhimurium changes inflammatory environ-ment in the intestinal layers, promoting
the composition of the microbiota and the permeability of the changes in the microbiota and promoting chronic diseases. It
epithelial barrier, which could be a trigger for the disease in would be relevant to evaluate whether IBD patients are chronic
susceptible individuals, given that these changes modify the carriers of S. Typhimurium in the intestine.
production of cytokines and SCFAs, produce an influx of
neutrophils and persistence infection of dendritic cells and, in

* Kaser A, Blumberg RS. Autophagy, microbial sensing, endoplasmic

reticulum stress, and epithelial function in inflammatory bowel disease.
Gastroenterology (2011) 140:1738–47. doi:10.1053/j.gastro.2011.02.048
Supporting the hypothesis raised in this review, it has been

* Neuman MG, Nanau RM. Inflammatory bowel disease: role of diet, micro-biota,
life style. Transl Res (2012) 160:29–44. doi:10.1016/j.trsl.2011.09.001
described that IBD patients have a deregulated immune response in
* Massironi S, Rossi RE, Cavalcoli FA, Della Valle S, Fraquelli M, Conte
the intestine, which is reflected for instance by the secretion of IgG
instead of IgA, resulting in an inflammatory response against their Nutritional deficiencies in inflammatory bowel disease: therapeutic
own microbiota (56). This loss of tolerance to the microbiota could approaches. Clin Nutr (2013) 32:904–10. doi:10.1016/j.clnu.2013.03.020
be determining factor to the infection with an invasive bacterium as
S. Typhimurium, which could promote a permanent inflammatory
response in the intestine, which in turn could bias the humoral
immune response to an IgG type to other bacteria, as the intestinal
microflora. It has been described that in IBD patients the
commensal microbiota has different phyla pro-portions in
comparison to a healthy person, having less amount of
Bacteroidetes and Firmicutes (beneficial bacteria) (56, 66, 67).
This allows less competition to pathogenic bacteria, making them
more invasive. On the other hand, in these patients, the epithelial
barrier is impaired because of inflamed epithelial cells, continu-ous
secretion of pro-inflammatory cytokines, and disrupted tight
junctions (54). It is possible that all these alterations could be due
to S. Typhimurium infection, which results in an increased
inflammation in susceptible patients (44, 46, 54).
It is known that S. Typhimurium can produce an inflamma-tory

environment due to virulence proteins coded by SPIs, which
improve its fitness over intestinal microbiota and, thereby, to reach
and invade the epithelium (79). Therefore, the inflamma-tion
would not be detrimental for this kind of invasive pathogen and
conversely it might be facilitating growth (41, 89, 128,
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McHugh G et al. Journal of the International AIDS Society 2017, 20:21843

http://www.jiasociety.org/index.php/jias/article/view/21843 | http://dx.doi.org/10.7448/IAS.20.1.21843
Research article
Clinical outcomes in children and adolescents initiating

antiretroviral therapy in decentralized healthcare settings in
Zimbabwe
Grace McHugh§*1, Victoria Simms*2, Ethel Dauya1, Tsitsi Bandason1, Prosper Chonzi3, Dafni Metaxa2, Shungu
Munyati1, Kusum Nathoo4, Hilda Mujuru4, Katharina Kranzer1,5 and Rashida A. Ferrand*1,2
§
Corresponding author: G. McHugh, Biomedical Research and Training Institute, 10 Seagrave Rd, Harare, Zimbabwe. (graceandandre@gmail.com)
*All authors contributed equally
Abstract
Introduction: Decentralized HIV care for adults does not appear to compromise clinical outcomes. HIV care for children poses
additional clinical and social complexities. We conducted a prospective cohort study to investigate clinical outcomes in children aged
6–15 years who registered for HIV care at seven primary healthcare clinics (PHCs) in Harare, Zimbabwe.
Methods: Participants were recruited between January 2013 and December 2014 and followed for 18 months. Rates of and
reasons for mortality, hospitalization and unscheduled PHC attendances were ascertained. Cox proportional modelling was
used to determine the hazard of death, unscheduled attendances and hospitalization.
Results: We recruited 385 participants, median age 11 years (IQR: 9–13) and 52% were female. The median CD4 count was
3
375 cells/mm (IQR: 215–599) and 77% commenced ART over the study period, with 64% of those who had viral load measured
achieving an HIV viral load <400 copies/ml. At 18 months, 4% of those who started ART vs. 24% of those who remained ART-naïve
were lost-to-follow-up (p < 0.001). Hospitalization and mortality rates were low (8.14/100 person-years (pyrs) and 2.86/100 pyrs,
respectively). There was a high rate of unscheduled PHC attendances (34.94/100 pyrs), but only 7% resulted in hospitalization.
3
Respiratory disease was the major cause of hospitalization, unscheduled attendances and death. CD4 count <350cells/mm was a
risk factor for hospitalization (aHR 3.6 (95%CI 1.6–8.2)).
Conclusions: Despite only 64% of participants achieving virological suppression, clinical outcomes were good and high rates
of retention in care were observed. This demonstrates that in an era moving towards differentiated care in addition to
implementation of universal treatment, decentralized HIV care for children is achievable. Interventions to improve adherence
in this age-group are urgently needed.
keywords: HIV; Africa; children; retention in care; outcomes
Received 17 January 2017; Accepted 18 August 2017; Published 1 September 2017
Copyright: © 2017 McHugh G et al; licensee International AIDS Society. This is an Open Access article distributed under the terms of the Creative Commons
Attribution 3.0 Unported (CC BY 3.0) License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited.
By 2015, an estimated 1.8 million children under 15 years of age

were living with HIV globally, the majority in Sub-Saharan Africa,
yet just half were accessing antiretroviral therapy (ART) [1].
Introduction
While the number accessing HIV treat-ment represents gains
from 2010, children lag disproportio-nately behind adults in
terms of ART coverage (49% of all children infected were
accessing ART in 2015 as compared to just 21% in 2010) [1].
access to care for patients and relieve pressure on heavily
As ART programmes have scaled up, the major barriers to ART overburdened secondary care facilities [9]. More recently,
access have been the lack of healthcare professionals to provide differentiated care initiatives are focusing on providing ser-vices
HIV care, overcrowding of clinics and distance to facilities where which are more client focused and tailored to specific needs of
such care is available [2–6]. Among adults, the increase in numbers diverse populations of people living with HIV [10]. Zimbabwe has
of individuals accessing ART has led to decentralization of HIV care incorporated the concept of differentiated care into its recent HIV
provision from second-ary to primary health care facilities, and task- treatment framework [11].
sharing to involve nurses in treatment of HIV infection [7,8]. The
aims of decentralization and task-sharing was to improve
Clinical outcomes among adults HIV care in decentralized
programmes with nurse-led care have been comparable to those in
secondary healthcare facilities [7,8,12,13]. Provision of HIV care to
children and adolescents is associated with additional complexities,
which may impact on clinical out-comes [9]. These include reliance
on guardians, who are often not biological parents, for access to
and retention in care, weight-based ART dosing, difficulties in
discussing HIV and disclosing HIV status to children [14–16]. Older
children and adolescents with HIV have higher rates of virological
fail-ure and attrition than adults [17,18]. These have led to a
1
Participants
Children aged between 6 and 15 years who tested HIV

relative reluctance by primary care level providers to positive through provider-initiated HV testing and
provide HIV care to this age-group [19]. WHO guidelines
now recom-mend “treat all” living with HIV and Zimbabwe,
since 2016, has adapted its national guidelines to reflect
this. Limited data are available on ART care provision to
children by nurses in primary health care facilities [20]. We
present clinical out-comes among children and
adolescents accessing decentra-lized HIV care services
provided by nurses in Harare, Zimbabwe.
Methods
Study setting
A prospective cohort study of children aged 6–15 years was

conducted in seven primary healthcare clinics (PHCs) in south
west Harare, Zimbabwe between January 2013 and
December 2014. Opt-out HIV testing and decentralized,
nurse-led HIV care for children was introduced at the seven
PHCs with supervision from by a physician. Children found to
be HIV positive were offered enrolment into the cohort which
was then followed over 18 months’ duration. Clinics where the
study was performed were treating adults with HIV infection
on a nurse-led basis as per Zimbabwe national guidelines but
had not been treating children living with HIV. Children were
followed up by research nurses for 18 months from time of
study enrolment. On completion of study follow up, HIV care
and management was transferred to clinic nursing staff.
Nurses in the employ of the clinic were trained on HIV care
and management for children over the duration of the study.
Although treatment and care was provided by research nurses
with a physician backup, national guidelines for treatment and
management of children living with HIV were used. Staff
within the primary health care clinics where our study was
performed, who similar to the model used in the study, have
physician support weekly and were trained on management of
paediatric HIV treatment in tandem with research nurses.
Details of the study which includes baseline clinical data at
time of enrolment have been described elsewhere [21].
Research nurses based at each clinic were trained on paedia-
tric HIV testing and counselling and provision of HIV care,
treatment monitoring and management of infections, based on
the Integrated Management of Childhood Illness (IMCI)
algorithm, over a 2-week period prior to study commence-
ment [22]. The Ministry of Health and Child Care training tools
were utilized and simple ART-dosing charts (available on
request) were produced to facilitate weight-based dosing.
Criteria for referral to secondary level facilities were pre-
defined, including “danger signs” based on the IMCI algo-
rithm. Nurses carried out ART eligibility screening, initiated
ART and provided follow-up care, supported by weekly visits
from a physician. Adherence counselling was provided by
primary care counsellors trained in paediatric HIV care. Each
visit to a PHC incurs a USD1 fee which is standard throughout
Zimbabwe. Cotrimoxazole and ART are provided free of
charge through the National ART Programme.
with primary healthcare and hospitalization since the pre-
vious visit (confirmed by patient-held records) and history
of incident infections.
counselling were enrolled into the cohort study (of Until February 2014, participants were ART eligible if
whom a proportion were simultaneously enrolled into 3
CD4 was below 350 cells/mm or they had evidence of
a rando-mized controlled trial to assess impact of WHO Stage 3 or 4 infections. ART regimens consisted of
household sup-port to children living with HIV[trial stavu-dine/lamivudine and nevirapine for children under 12
registry number PACTR201212000442288]), if they years or tenofovir/lamivudine and nevirapine if over 12
chose to access HIV care at the clinic where they years of age. Efavirenz was substituted for nevirapine in
were diagnosed and gave consent [23]. case of concomitant TB treatment or nevirapine allergy.
From March 2014, Zimbabwe adopted the WHO 2013
consoli-dated guidelines with the threshold for ART
3
Study procedures initiation revised to 500 cells/mm and ART regimes were
standar-dized to zidovudine/lamivudine and nevirapine for
those under 12 years and not requiring TB treatment, and
At the initial assessment visit within a week of HIV diag- teno-fovir/lamivudine and efavirenz for those over 12 years
nosis, socio-demographic data, past clinical history and of age [26]. CD4 count was performed 6 monthly for all
current symptoms were assessed, and a standardized participants. HIV viral load testing was performed at 48
examination performed. Participants underwent WHO weeks post ART commencement using COBAS
Staging and a CD4 count, using Alere Pima™ CD4 Ampliprep/Taqman 48 Version 2.0.
machine, was measured [24]. All participants underwent
counselling and were started on cotrimoxazole.
Unscheduled visits were defined as visits occurring out-side
Participants who screened positive on the WHO TB
the scheduled visits for either a medical or non-med-ical
screen had sputum examined onsite by Ziehl–Neelsen
reason (e.g. counselling). Side effects were graded according
smear microscopy and Xpert TB™ [25]. Participants were
to the DAIDS grading system [27].Hospitalization was defined
seen within 2 weeks of the initial visit to assess
as a participant spending one night or more in a hospital. If a
adherence and determine side effects of cotrimoxazole,
participant had more than one hospitaliza-tion, they were
and to commence ART if eligible. The schedule for follow
counted separately even if related to the same clinical issue.
up was based on national guide-lines, with visits at 2 and
Transfer out was defined as a caregiver informing the clinic of
6 weeks post ART commencement and then on a 3-
the participant changing care to another clinic and a transfer
monthly basis. Participants not eligible for ART at
letter being provided. Participants who failed to attend more
baseline underwent a 3-monthly symptom-based review
than two scheduled
and examination to reassess ART eligibility. At each visit,
a standard proforma was used to collect information on
current symptoms, side effects of ART, history of contact
2
At the end of 18 months, 286 (74%) were still in care, 50

(13%) had transferred to another clinic, 12 (3%) moved to
another clinic without informing clinic staff, 9(2%) moved
appointments were traced through a phone call and/or a away and did not transfer to another clinic, 13 (3%) died, 1
home visit. Participants were defined as having moved withdrew from the study after initial assessment and 14
away if they had moved care to another clinic without (4%) were LTFU (Table 2). Importantly, those who did not
informing clinic staff. Participants were deemed lost to
follow-up (LTFU) if they could not be traced. Tracing was
performed at clinic level by research nurses who phoned
the participant’s guardian on 2 occasions if a participant
had not returned for a visit within 3 months of the sched-
uled date. If after the second phone call a participant could
not be reached then a voluntary lay health worker visited
the house. If a participant died, the cause of death was
determined through hospital records. In the case of death
occurring outside of hospital, this was confirmed through
verbal autopsy with the caregiver.
Data management and analysis
Data was extracted from paper forms using optical mark

recognition software (Cardiff TELEFORM Intelligent
Character, Version 10.7) and analysed using STATA, version
12.1 (STATA Corporation, USA). Stunting and wasting were
defined as a height-for-age z-score and a weight-for-age z-
score of <-2, respectively [28]. Rates of hospitalization,
unscheduled visits and death were calculated. Cox propor-
tional modelling was used to determine the hazard of death,
unscheduled visits and hospitalization, controlling for factors
found to be significantly associated with the outcome in
univariate analysis.
Ethical considerations
Written informed consent was obtained from all caregivers

and written assent obtained from participants. Ethical
approval for the study was obtained from the Medical
Research Council of Zimbabwe, the Harare City Health
Department Ethics Committee, the Biomedical Research
and Training Institute Institutional Review Board and the
London School of Hygiene and Tropical Medicine Ethics
Committee.
Results
A total of 385 participants were enrolled into the study

and provided 450 person-years of follow up and a
median of 504 days (IQR 1–515). The median age at
HIV diagnosis was 11 years (IQR 9–13) and 52% were
female. Most partici-pants were infected with HIV
through mother-to-child transmission, and 59% were
single or double orphans (Table 1). The median CD4
count at HIV diagnosis was 375 cells/mm 3 (IQR 215–
599). Over the 18-month period, 296 (77%) participants
commenced ART, 70% of whom did so within 4 weeks
of enrolment (Table 1). Of the 89 parti-cipants who did
not initiate ART, 7 were eligible according to national
guidelines and 82 were not eligible during follow-up.
Median days on ART for those who initiated 485 (359–495)
(IQR)
Table 1. Baseline characteristics of enrolled participants at

baseline (N = 385)
Characteristic N
start ART were significantly more likely to be LTFU than
those who started ART (p < 0.001). CD4 counts for those
Age (years), median (IQR) 11 (9,10,11,12,13) who commenced ART increased over the follow-up period,
Female 199 (52%) with those who did not start ART (n = 89) maintaining their
CD4 counts (Figure 1). Of those who commenced ART
3 within 24 weeks of enrolment into the study (n = 273), 200
Median (IQR), CD4 cells/mm 375 (215–599)
had a viral load sample collected between 40 and 72
3
CD4< 350 cells/mm 177 (46%) weeks post ART, with 195 results obtained. 124 (64%) of
those whose viral load result was obtained had a viral load
3
CD4 350–500 cells/mm 74 (19%) <400 copies/ml.
3
CD4> 500 cells/mm 131 (34%)
WHO Stage 3 or 4 Unscheduled visits

Mode of HIV acquisition 155 (40%)
Mother-to-child 369 (96%) There were 146 unscheduled visits made by 99 participants
over the follow-up period, equivalent to a rate of 34.94/100
Horizontal 13 (3%) person years (95% CI 29.70–41.09). Ten unscheduled visits
Unknown 3 (1%) resulted in hospitalization, all of whom were receiving ART.
The most common reason for an unscheduled attendance to
Orphanhood 157 (41%) the clinic was illness (n = 133, 91%). Other reasons included
medication collection (n = 5, 3%) and additional adherence
Both parents alive 77 (20%)
counselling (n = 8, 6%). The major cause of illness leading to
Maternal Orphan/Father Alive 71 (18%) an unscheduled visit was respiratory tract infection
(responsible for 45% of unscheduled visits due to illness),
Paternal Orphan/Mother Alive 58 (15%) followed by skin infections which accounted for 22% of
Double Orphan 22 (6%) unscheduled visits due to illness (Table 3).
Unknown status of either parent

Side effects from ART resulted in unscheduled visits in 20
Biological parent as the current caregiver 220 (57%) patients (15% of unscheduled visits due to illness). Of these,
Grade 1 nevirapine hypersensitivity was the most common
Started ART within 4 weeks of enrolment 206 (54%)
Started on ART over 18-month follow up 296 (77%)
3
Table 2. Outcomes at 18 months of cohort participants by ART initiation status
Total Initiated ART over follow Did not initiate ART over P-
N = 385 up period N = 296 follow up period N = 89 value
In care to end of study follow up 286 (74.3%) 243 (82.1%) 43 (48.3%) <0.01
Planned transferred to another clinic 50 (13.0%) 30 (10.1%) 20 (22.5%) <0.01

a
Left area without transfer of care 9 (2.3%) 2 (0.7%) 7 (7.9%) <0.01
a
Not in care and untraceable 14 (3.6%) 6 (2.0%) 8 (9.0%) <0.01
No planned transfer, but was found 12 (3.1%) 3 (1.0) 9 (10.1) <0.01
in care at another clinic
Withdrew from study 1 (0.3%) 0 (0.0%) 1 (1%) 0.06
Died 13 (3.4%) 12 (4.1%) 1 (1%) 0.18
a
ascertained through phone calls and home visits.
800
700
600
)
3
/MM
500
(CELLS
400
COUNT
300
CD4
200
100
0
BASELINE 24 WKS 48 WKS 72 WKS
TIME FROM ENROLMENT
NOT ON ART ON ART
Figure 1. Median CD4 count over 18 month follow up by ART status.
side-effect (n = 8). Only one participant was hospitalized due

to ART side effects-for rehydration secondary to grade 3 participants diagnosed through sputum testing using
vomiting. Other ART side effects reported at routine 3-monthly geneXpert or based on chest X-ray findings. Six participants
follow up were uncommon and self-limiting-consist-ing of were hospitalized more than once for the same clinical
nausea (6%), vomiting (6%), abdominal pain (3%), diarrhoea diagnosis (1 admitted twice for HIV-related anaemia, 1
(6%), fatigue (5%), rash (3%), jaundice (0.1%), dizzi-ness admitted twice for lower respiratory tract infection, 1 admitted
(3%) vivid dreams (2%), and confusion (1%). Overall, side twice for Steven Johnson’s syndrome secondary to
effects of ART resulted in drug switches in 11 cases (n = 9 cotrimoxazole due to ongoing symptoms, and 1 admitted
due to nevirapine hypersensitivity, n = 1 anaemia due to thrice for recurrent lower respiratory tract infection). Two
zidovu-dine and n = 1 grade 3 efavirenz hypersensitivity participants were admitted twice but for different clinical
reaction). Such switches were managed in the primary care events. Only three hospitalizations occurred in participants not
clinics by nursing staff with consultation from study physician. taking ART, two of which were due to malaria. Only one was
HIV related, namely HIV-associated anaemia and
thrombocytopenia, and resulted in death. The CD4 count at
hospitalization in this participant was 1114 cells/mm3.
Hospitalizations
Deaths
There were 34 hospitalizations in 27 participants, 9 of which
resulted in death. The rate of the hospitalization was 8.14/100
person years (95% CI 5.81–11.39). Lower respiratory tract The mortality rate was 2.86/100 pyrs (95% CI 1.65–4.95). Of
disease was commonest reason for admis-sion (Table 4). TB the 13 deaths in the cohort, 12 occurred in hospital and
was the cause of hospitalization in 8 respiratory disease was the most common cause (Table 5).
4
The median CD4 count at enrolment of those who died was 73

cells/mm3 (IQR 12–205) and 77% of those who died had WHO
Stage 3 or 4 disease at enrolment. The median time from
enrolment to death was 76 days (IQR 59–410).
Table 3. Reasons for unscheduled visits due to illness
(N = 133) A CD4 count less than 350 cells/mm3 at enrolment, WHO

stage 3 or 4 HIV disease and wasting were asso-ciated with
hospitalization and death on univariate analy-sis (Table 6). CD4
Cause of unscheduled attendance N (%) count less than 350cells/mm3 and advanced WHO stage
remained significantly associated with the outcome in
multivariate analysis for hazard of hospitalization (aHR 3.6
Respiratory tract infection 60 (45%) (95%CI 1.6–8.2), aHR 2.6 (95% CI 1.1–6.2)), no variables
Upper respiratory tract infection 27 remained significantly associated with the hazard of death.
Being older (HR 2.1 (95%CI 1.4–3.1), WHO stage 3 or 4
Lower respiratory tract infection 16 disease (HR 1.5 (95% CI 1.0–
Pulmonary TB 11
2.1) and wasting (HR 1.8 (95% CI 1.3–2.7)) were associated
Otitis Media 2
with having unscheduled visits due to illness. On multi-
Tonsillitis 4 variate analysis, association with being in an older age
group (aHR 1.9 (95%CI 1.3–3.1)) and wasting (aHR 1.8
Skin infections 29 (22%) (95%C.I 1.0–2.3)) remained significant.
Oro-labial Herpes Simplex 5
Herpes Zoster 5
Chicken Pox 1
Bacterial skin infection 15
Fungal skin infection (Tinea capitis or corporis) 2
Papular pruritic eruption 1
Gastrointestinal disease 16 (12%)
Gastroenteritis 9
Chronic diarrhoea 2
Hepatitis A 1
Oral candidiasis 3
Oesophageal candidiasis 1
Antiretroviral therapy side effects 20 (15%)
Grade 1 Nevirapine hypersensitivity 8
Grade 2/3 NNRTI skin hypersensitivity 8
Grade 2/3 vomiting 3
Anaemia 1
Miscellaneous 8 (6%)
Minor trauma 1
Gingivitis 2
Conjunctivitis 2
Mumps 1
TB lymphadenitis 2
Lower respiratory tract infection 4 (31)
Malignancy – CNS lymphoma 1 (7)
Congestive cardiac failure 1 (7)

Table 4. Causes of hospitalization (N = 34)
Meningitis 1 (7)
Accidental drowning 1 (7)
Anaemia/Thrombocytopenia 1 (7)
Cause of hospitalization N (%)
Respiratory Illness n = 18 (53%)
Pulmonary TB 7
Discussion
Disseminated TB 1
Our study demonstrated that nurse-led HIV care for children
Lower respiratory tract infection 9
and adolescents is possible in primary care settings. The rate
Pneumocystis jiroveci pneumonia 1 of retention in care was comparable to that reported in facility-
based settings and higher than a recent retrospective cohort
Neurological Illness n= 5 (15%) review of children attending decentralized care in Swaziland
[20,29]. Provision of HIV care in primary care facilities reduces
Bacterial meningitis 1 the distance that patients need to travel to access treatment,
and this may help improve retention in care [3,20]. Notably,
Cryptococcal meningitis 2
the rate of retention in care was sig-nificantly lower in those
who did not start ART, with half of those who did not initiate
CNS lymphoma 1
ART being LTFU. This finding has been reported previously
Seizure (cause unknown) 1 and may be because patients per-ceive no benefit in attending
for care if they are not
Miscellaneous n = 11 (32%)
Hyperglycaemia 1
a
Anaemia 3
Congestive Cardiac Failure 1
Gastroenteritis 1
Vomiting Secondary to ART 1
b
Malaria 2
Stevens–Johnson syndrome secondary to 2
cotrimoxazole
Numbers refer to hospitalization events rather than numbers of

a b
participants admitted, n = 1 not on ART, n = 2 not on ART
Table 5. Causes of death amongst cohort participants over 18

month follow up (N = 13)
Cause of death N (%)
Pulmonary TB 4 (31)
5
Table 6. Cox proportional hazard ratio for hospitalization, unscheduled visit due to illness and death
Hospitalization Unscheduled visit
N = 34 N = 118
Crude hazard Crude hazard
a
Total N Rate (95% CI) ratio AHR N Rate (95% CI) ratio
Age 11–15 200 17 7.7 (4.8–12.5) 0.9 (0.5–1.8) - 82 37.3 (30.1–46.4) 2.1 (1.4–3.1)
6–10 185 17 8.6 (5.3–13.8) 1 36 18.2 (13.1–25.2) 1
Sex Female 199 15 6.9 (4.2–11.5) 0.7 (0.4–1.4) - 68 31.4 (24.7–39.8) 1.3 (0.9–1.8)
Male 186 19 9.44 (6.0–14.8) 1 50 24.9 (18.8–32.8) 1
CD4 at <350 177 26 13.1 (8.9–19.3) 4.1 (1.8–9.4) 3.6 (1.6–8.3) 65 32.8 (25.7–41.8) 1.4 (0.9–1.9)
b
enrolment >350 205 7 3.2 (1.5–6.8) 1 53 24.5 (18.7–32.0) 1
WHO stage 3–4 155 25 14.8 (10.0–21.9) 4.0 (1.9–8.6) 2.6 (1.1–6.2) 59 34.9 (27.1–45.1) 1.5 (1.0–2.1)
1–2 230 9 3.6 (1.9–6.9) 1 59 23.7 (18.4–30.6) 1
ART within Y 206 22 9.2 (6.1–14.0) 1.4 (0.7–2.9) - 69 28.9 (22.8–36.5) 1.1 (0.75–1.6)
4 weeks N 179 12 6.7 (3.8–11.8) 1 49 27.3 (20.0–36.6) 1
Stunting Y 91 13 13.0 (7.5–22.4) 1.9 (1.0–3.8) - 31 31.0 (21.8–44.1) 1.1 (0.74–1.7)
N 294 21 6.6 (4.3–10.1) 1 87 27.4 (22.2–33.8) 1
Wasting Y 105 19 17.3 (11.1–27.2) 3.5 (1.8–6.8) 2.1 (1.0–4.5) 47 42.9 (32.2–57.1) 1.8 (1.3–2.7)
N 280 15 4.9 (2.9–8.1) 1 71 23.0 (18.3–29.1)
a
Adjusted for factors significantly associated with the outcome in univariate analysis; AHR: adjusted hazard
b
ratio; data missing for n = 3
nature of TB in children. TB preventative therapy using

isoniazid prophylaxis had not been widely implemented in
Zimbabwe at commencement of the study and no
receiving treatment [30,31]. The 2015 WHO guidelines

recommend initiation of ART regardless of disease stage
or age and this may facilitate retention in care [32].
Worryingly, only two-thirds of children achieved virologi-cal

suppression after starting ART, similar to the proportion
reported in a recent study in a clinic in a central hospital in
Harare [33]. Other studies have demonstrated virological
suppression rates ranging from 27 to 89% in adolescents [34].
Notably, 172 (44.7%) of our study cohort received community
lay worker support due to participation in a randomized
controlled trial which may have potentially increased the
proportion of participants with viral load suppression. There
were no drug-stock outs over the dura-tion of our study and so
the virological unsuppressed rate most likely reflects
suboptimal adherence. Since study com-pletion, viral load
testing has become available at primary care clinics within
Zimbabwe’s health service. Children are expected to take
ART for at least two decades longer than adults and the need
for interventions in this age-group to support sustained
adherence to minimize emergence of drug resistance cannot
be over-emphasized, particularly in resource-limited settings
where options for second and third-line ART are limited.
Despite a good immunological response to treatment, a

high frequency of PHC attendances occurred outside
sched-uled clinic appointments. Most unscheduled
presentations were, however, due to minor illness and
were managed at primary care level, with only a minority
resulting in referral to hospital for further management.
Such referrals were decided on due to the nature of the
limited services pri-mary care health facilities are able to
provide in the event of more serious illness. Decentralized
HIV care therefore provides a system for triage and
reduces the burden on secondary health facilities, making
it a sustainable system for chronic care provision.
The leading cause of unscheduled visits, hospitalization

and death was respiratory tract infections, even among
patients on ART. We have previously reported a high bur-
den of chronic lung disease in perinatally infected children
and adolescents, which is associated with considerable
morbidity including recurrent respiratory tract infections,
poor lung function and reduced exercise tolerance [35].
The recurrent respiratory tract infections observed in this
study may be due to underlying chronic lung disease. The
pathogenesis is poorly understood but is thought to be a
sequela of chronic infections and/or HIV-mediated chronic
inflammation. Once established chronic lung disease
appears to be poorly responsive to ART, and children with
recurrent respiratory tract infections may require further
interventions such as additional prophylactic antibiotics or
anti-inflammatory agents [36].
Notably, 8 hospitalizations were TB related, 4 of them

resulting in death, despite active case finding at baseline
through sputum testing and at follow up through WHO
symptom screening. This demonstrates the low sensitivity of
the WHO TB screening tool, and reflects the paucibacil-lary
Older age was associated with more frequent unscheduled
visits but not death and hospitalization. This might reflect a
combination of survival bias and longer life-time exposure of
uncontrolled viremia. While these children survived into ado-
lescence without major illness, the uncontrolled viremia may
participant received it over the study period. Skin disease
have resulted in a higher prevalence and more prominent
was the second most common cause of unscheduled
chronic disease phenotype such as chronic lung disease.
visits to PHCs. Recurrent skin infections are strongly
associated with HIV infection in children, and in high HIV
prevalence settings should prompt HIV testing [37,38]. The strengths of the study were the prospective design and that
Side effects of ART accounted for only 15% of participants were actively followed up to ascertain out-comes.
unscheduled attendances. Importantly, most patients Detailed clinical data were collected to establish the reasons for
with side effects were managed in primary care visits to health facilities and cause of death. The study was
necessitating few drug switches, all effected at primary conducted in public sector services and therefore the findings are
care level. broadly generalizable. Limitations include the lack of viral load
data in all participants (73% of those eligible had viral load
measured). There is a risk that the Cox propor-tional hazard
As has been reported in other studies, advanced disease
models for death and admission may be over-fitted due to a small
stage and immunosuppression were risk factors for both
number of events. To mitigate this risk, no variables were
hospitalization and death [39,40]. The median CD4 count at
specified a priori. Diagnoses such as respiratory tract infections
diagnosis was 375 cells/mm3, and the median age at diag- were made in PHC were based on symptoms and clinical
nosis in a cohort where nearly all participants were infected examination, as diagnostic facilities are limited.
perinatally was 11 years, implying an average delay of a
decade in diagnosing HIV infection. Given the high HIV-
associated mortality observed in infants, there is limited
awareness that a third of HIV-infected infants survive to
adolescence even without treatment [41]. Therefore, HIV Conclusions
testing is only offered when children present with condi-tions
indicative of HIV infection, by which time they have often
developed advanced disease [19,29]. However, at least a Our study shows that decentralized nurse-led HIV care for
quarter of children retained high CD4 counts (>500 children is possible and results in clinical outcomes compar-
able to those reported in children elsewhere in southern Africa
cells/mm3) and remained ineligible for ART based on cur-
[20]. Implementation of 2015 WHO guidelines that
rent national guidelines. While a sub-group of these may be
recommend universal treatment of all HIV-infected indivi-
true long-term non-progressors or elite controllers, many
duals, is likely to result in a substantial increase in children
remain pauci-symptomatic and may not prompt healthcare
workers to offer HIV testing [33,34]. eligible for treatment, particularly given the current low ART
coverage. Considerable investment in age-appropriate HIV
7
3. van Dijk JH, Sutcliffe CG, Munsanje B, Hamangaba F, Thuma PE,

Moss WJ. Barriers to the care of HIV-infected children in rural Zambia: a cross-
sectional analysis. BMC Infect Dis [Internet]. 2009 Jan [[cited 2016 Feb 23];9:169.
Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=
testing strategies, training and support for primary health care 2767351&tool=pmcentrez&rendertype=abstract
providers and interventions to support adherence need to be
strengthened to achieve universal access and optimum 4. van Dijk JH, Moss WJ, Hamangaba F, Munsanje B, Sutcliffe CG.
treatment outcomes among children and adolescents. Scaling-up access to antiretroviral therapy for children: a cohort study
evaluating care and treatment at mobile and hospital-affiliated HIV clinics in
rural Zambia. PLoS One [Internet]. 2014 Jan [cited 2016 Feb
23]];9(8):e104884. Available from:
Authors’ affiliations http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=
4133342&tool=pmcentrez&rendertype=abstract
1
Biomedical Research and Training Institute, Harare, Zimbabwe;
2 5. Vermund SH, Blevins M, Moon TD, José E, Moiane L, Tique
Department of Infectious Disease Epidemiology, London School of Hygiene
3 JA, et al. Poor clinical outcomes for HIV infected children on antiretroviral
and Tropical Medicine, London, UK; Directorate of Health Services, Harare
4 therapy in rural Mozambique: need for program quality improvement and
City Health, Harare, Zimbabwe; Department of Paediatrics, University of community engagement. Dowdy DW, editor. PLoS One [Internet]. Public
5
Zimbabwe, Harare, Zimbabwe; National and Supranational Reference Library of Science;2014 Jan [cited 2014 Oct 23];9(10):e110116.
Laboratory, Research Centre Borstel, Germany
doi:10.1371/journal. pone.0110116
6. Kimani-Murage EW, Manderson L, Norris SA, Kahn K. “It’s my

Competing Interests secret”: barriers to paediatric HIV treatment in a poor rural South African
setting. AIDS Care [Internet]. Taylor & Francis;2013 [cited 2016 Nov
18];25(6):744–
The authors have no conflict of interests 47. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/23244783
7. Fairall L, Bachmann MO, Lombard C, Timmerman V, Uebel K, Zwarenstein M, et

al. Task shifting of antiretroviral treatment from doctors to primary-
Author’s Contributions
RAF designed the study. GMCH and ED supervised data collection.

GMCH and VS analysed the data. GMCH wrote the first draft of the
manuscript. All authors contributed to the writing of the manuscript.
The funders had no role in study design, data collection and analysis,
decision to publish, or preparation of the manuscript. The authors have
no conflict of interest.
Acknowledgements
We wish to acknowledge the study participants, their caregivers and

our dedicated research nurses and assistants.
Funding
The study was funded by the Wellcome Trust though an Intermediate

Fellowship Grant (095875/Z/11Z) awarded to RAF. The authors have
no conflict of interests.
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9
International Surgery Journal | March 2017 | Vol 4 | Issue 3
Page 931
LAMPIRAN

Jurnal Prognosis

Diunggah oleh

Informasi Dokumen

Judul Asli

Hak Cipta

Format Tersedia

Bagikan dokumen Ini

Bagikan atau Tanam Dokumen

Opsi Berbagi

Apakah menurut Anda dokumen ini bermanfaat?

Apakah konten ini tidak pantas?

Hak Cipta:

Format Tersedia

Jurnal Prognosis

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Hak Cipta:

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JURNAL PROGNOSIS

Ns. Nur Isnaini,S.Kep.,M.Kep.

Disusun Oleh Kelompok 10 Kep S1 4A

PROGRAM STUDI KEPERAWATAN S1

A. JURNAL PROGNOSIS SISTEM PENCERNAAN

3. Latar Belakang Temuan Jurnal :

5. Hasil dan Pembahasan :

B. JURNAL PROGNOSIS SISTEM PERKEMIHAN

3. Latar Belakang Temuan Jurnal :

4. Metode & hasil :

C. JURNAL PROGNOSIS SISTEM ENDOKRIN

3. Latar Belakang Temuan Jurnal :

5. Hasil dan Pembahasan :

D. JURNAL PROGNOSIS SISTEM IMUNOLOGI

3. Latar Belakang Temuan Jurnal :

5. Hasil dan Pembahasan :

Babu KS et al. Int Surg J. 2017 Mar;4(3):929-931

http://www.ijsurgery.com pISSN 2349-3305 | eISSN 2349-2902

A study on acute appendicitis in a tertiary care hospital in

Tamil Nadu, India

K. Suresh Babu*, S. Savitha

Received: 25 January 2017

Accepted: 04 February 2017

Dr. K. Suresh Babu,

International Surgery Journal | March 2017 | Vol 4 | Issue 3 Page 929

Total 100 100

Out of 100 patients, 55% were male and 45% were

Table 1: Distribution of age and sex of the study

Age (years ) Male Female Total Percentage

Total 55 45 100 100

Table 2: Distribution of position of appendix.

Position Number Percentage

Funding: No funding sources

International Surgery Journal | March 2017 | Vol 4 | Issue 3 Page 930

4. Chaudhari YP, Jawale PG. Prevalence of

5. Kamath P. A clinico pathological study of 7. Jess P, Bjerregaard B, Brynitz S, Christensen J,

European Journal of Heart Failure (2017) 19, RESEARCH

Associations with and prognostic

numerous trials in HFrEF have established the efficacy

*Corresponding author. Tel: +46708744502, Fax: +46858583124; Email: ida.haugen-lofman@sll.se

© 2017 The Authors

European Journal of Heart Failure © 2017 European Society of Cardiology

. ... ... ... ..

... ... ...

understood. There are no studies specifically comparing HFpEF, 5,17

The study conforms to the declaration of Helsinki and was approved

differentiate between HFpEF and HFrEF,11 included highly selected

by the regional ethics review board in Linköping.

© 2017 The Authors

is a web-based national quality register that has enrolled unselected HF

are available online (http://www.SwedeHF.se).

Inclusion criterion is clinician-judged HF, and approximately 80

variables are recorded at discharge from hospital or during outpatient

visits to physician or healthcare team. Individual patient consent is

registers and allowed to opt out.

Associations between baseline variables and baseline CKD were

Figure 1 Patients included in the study from the Swedish Heart

the Swedish population registry, which includes the vital status of

Table 1 Baseline characteristics in absence and presence of chronic kidney disease

pEF/mrEF/rEF (n = 3908, (n = 4967, (n = 4393, (n = 3981, (n = 12607, (n = 10 374,

44.0%) 56.0%) 52.5%) 47.5%) 54.9% 45.1%)

Variables are median (interquartile range) or per cent.

† The 28 variables in the multiple imputation and multivariable analyses.

† * * ***