nocardiosis in the south of france during the last ten years

Four clinical presentations depending on the underlying condition were identified: disseminated forms 50.0% and visceral isolated forms 26.5% in severe immunocompromised patients, bonchi

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Title: Nocardiosis in south of France during the last ten years

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France during the last ten years.International Journal of Infectious Diseases

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Nocardiosis in south of France during the last ten years

Running head: nocardiosis and clinical forms

Delphine Haussaire1*delphaus@aol.com, Pierre-Edouard Fournier2, Karamoko Djiguiba1, Valerie Moal1, Tristan Legris1, Rajsingh Purgus1, Jeremy Bismuth3, Xavier Elharrar4, Martine Reynaud-Gaubert3, Henri Vacher-Coponat1**Henri.VACHERCOPONAT@ap-hm.fr

1

Department of Nephrology, AP-HM, Aix-Marseille University, Hôpital de la

Conception 147, boulevard Baille 13385 Marseille cedex 5, France

2Department of Infectious Diseases, AP-HM, Aix-Marseille University, Hôpital de la Timone, 264 rue Saint-Pierre, 13005 Marseille, France

Corresponding autor :Service de Néphrologie, Hôpital de la Conception 147,

boulevard Baille 13385 Marseille cedex 5, France,

**

Corresponding autor :Service Service de Néphrologie, Hôpital de la Conception

147, boulevard Baille 13385 Marseille cedex 5, France

Highlights:

 Clinical presentation of nocardiosis depend on immune status and underlying condition

 Severe forms in our study all occurring after treatments altering the immune system

 In our cohort, 38% of patients required both medical and surgical treatment

Abstract

Background:Nocardiosisis a raredisease with polymorphic presentations Epidemiology and clinical presentation could change with the increasing number of immunocompromised patients

Methods: Medical records and microbiologic data forpatients affected by nocardiosis

and treated in the university hospital of Marseille between 2004 and 2014 were retrospectively analyzed

Results:We analyzed34 patients infected by Nocardia spp during this period The

main underlying conditions were: transplantation (15), malignancy (9), cystic fibrosis (4) and immune disease (3) No immunodeficient condition was observed for 3 patients No AIDS case was observed At diagnosis, 61.8 % had received steroids for over 3 months Four clinical presentations depending on the underlying condition were identified: disseminated forms (50.0%) and visceral isolated forms (26.5%) in severe immunocompromised patients, bonchial forms (14.7%) in patients with chronic lung disease and cutaneous isolated forms (8.8%) in immunocompetent

patients N.farcinica was the main observed strain (26.5%)

Trimethoprim-sulfamethoxazole was prescribed in 68.0% of patients, and 38.0% had

surgery.Mortality was 11.7%, concerning patients with disseminated or visceral nocardiosis

Conclusion:Clinical presentation and evolution of nocardiosis depend on initial

immune status and pulmonary underlying condition Severe forms were all iatrogenic, occurring after treatments altering the immune system

Abbreviations

AIDS: Acquired Immune Deficiency Syndrome

AM: Antimetabolite

ANCA: AntiNeutrophil cytoplasmic antibodies

AP-HM: Assistance Publique des Hôpitaux de Marseille

BAL: Bronchoalveoloar liquid

BMT: Bone marrow transplantation

CAP CT: Chest, abdomen and pelvis computed tomography

CLL: Chronic Lymphocytic Leukemia

CNI: Calcineurin Inhibitor

CNS: Central Nervous System

CRP: C Reactiv Proteine

CT: computed tomography

GVHD: graft versus host disease

HBP: High Blood Pressure

HIV: Human Immunodeficiency Virus

NHL: Non Hodgkin’s Lymphoma

SOT: Solid Organ Transplantation

TMP-SFZ: Trimethoprim-Sulfamethoxazole

Keywords: nocardiosis, transplantation, cancer, cystic fibrosis, opportunistic infection

BACKGROUND

Nocardia spp are aerobic actinomycetes distributed worldwide,found in soil,

decaying vegetation and water, which may be pathogenic for human beings Their transmission mainly results from inhalation of spores, or direct inoculation 1

Nocardia spp cause localized or invasive infection leading to long-term treatment

and surgery and may occasionally be fatal Nocardiosis are usually reported in immunocompromised patients with AIDS, malignancy, solid organ transplantation (SOT), or long-term steroid therapy234.It rarely affects patients without any serious underlying condition56

Nocardia spp can be isolated with standard microbiological culture in various

samples like sputum, bronchoalveolar liquid (BAL), abscess, blood culture and then

identified by genotypic study Nowadays, up to 80 species of Nocardiasppare known

Nocardia asteroides was one of the first predominant strain identified and now

corresponds to several complexes: N.abscessus, N.brevicatena/pauciverans,

N.cyriacigeorgica, N.farcinica, N.nova, and N.wallacei78

Some series of nocardiosis are described910111213141516but few recent studies investigated nocardiosis epidemiology since improvement in treatment of HIV

infection, immune diseases or in the field of transplantation, which could have changed patient characteristics with nocardiosis

We reviewed all cases of nocardiosis diagnosed during the past 10 years in Marseille University Hospitals, to study their demographic, clinical, biological and

bacteriological characteristics, their treatment and prognosis

MATERIALS AND METHODS

Retrospectively, we analyzed all cases of nocardiosis identified between 2004 and

2014 in the microbiology laboratory of the university hospital of Marseille (4 hospitals belonging to the Assistance Publique des Hôpitaux de Marseille; AP-HM)

Our institution treats more than 120,000 patients per year,for a regional population estimated at 3,398,906 persons in 2014 During this period, 2,229 solid organ transplantations have been performed including 1,144 kidney, 520 liver, 263 adult lung, 236 heart and 11 heart-lung transplantations

We collected data from the corresponding medical records using a standardized questionnaire Demographic and underlying conditions analyzed were: gender, date

of birth, age at nocardiosis diagnosis, history of cancer, transplantation, immune

disease or HIV infection, history of any opportunistic infection (cytomegalovirus disease, aspergillosis, Pneumocystis carinii infection), and history of acute rejection

in transplanted patients Treatment at diagnosis was also reported:

immunosuppressive drugs, steroids and Trimethoprim-sulfamethoxazole (TMP-SFZ)

prophylaxis for Pneumocystis pneumonia

Clinical, biological, radiological data at diagnosis and outcomes were recorded: fever, cough, dyspnea, expectoration, pain, confusion, neurological deficit, coma, seizures, C Reactive Protein (CRP) level, complete blood count, T lymphocytes

count, source of bacteriological diagnosis, Nocardia spp strain and antibiotics

susceptibility, treatment, cure, functional sequellae, recurrence and death

Bacteriological study

Nocardia spp were cultivated from clinical specimen and all strains were indentified

using 16s rRNA by gene polymerase chain reaction The sequences obtained were compared with those stored in GenBank Strains had to have >99% sequence similarity with one species only Sequencing of the Hsp65 gene was also performed

to separate similar species, as previously described17

Antibiotic susceptibility was tested by disk diffusion We reported TMP-SFZ and carbapenem susceptibility only, the most commonly used antibiotics when nocardiosis is suspected (7)

RESULTS

From January 2004 to January 2014, 41 cases were identified in the microbiological laboratory data base Among them, 36 patients had beenhospitalized at AP-HM hospital including 34 patients with available medical records (table 1: general view of the 34 patients with nocardiosis) The data concerning the 7 patients with medical record missing are reported in supplementary material.(TableS1: 7 patients, nocardia strains, source of diagnosis, antibiotic susceptibility)

History of allograft was the main underlying condition (44.1%) observed in 14 patients with SOT, mean age 56.1 years (8 kidneys, 4 lungs, 1 liver and 1 heart) and one 9 years old girl with bone marrow transplantation (BMT) performed for an acute lymphocytic leukemia All received an immunosuppressive regimen: 11 triple therapy including a CNI, AM and steroids; 4 regimens with CNI and steroids An episode of acute rejection was reported in 28.0% patients before nocardiosis diagnosis and opportunistic disease in 35.7% No patient had TMP-SFZ prophylaxis at

diagnosis.Mean delay between transplantation and nocardiosis diagnosis was 17.5 months (2 to 34 months) with 9.4 months after lung transplantation; 16.5 months after renal transplantation The incidence of nocardiosis was 15.2/1000 lung transplantations (4/263), 7/1000 kidney transplantations (8/1144), 4.2/1000 heart transplantations (1/236), 2/1000 liver transplantations (1/520) (See table S2 in supplementary material)

A history of malignancy was observed in 9 patients (mean age 73.7 years): solid cancer in 4 (carcinoma of the ampulla of Vater and anal cancer with surgical treatment, metastatic breast cancer, one patient with 2 solid cancers (glioblastoma and non small cell lung cancer), haemopathy in 4 patients (Waldenstrom disease, non Hodgkin’s lymphoma (NHL), chronic lymphocytic leukemia (CLL), dysmyelopoietic syndrome) The last one had a haemopathy and a solid cancer (rectal adenocarcinoma and NHL) At diagnosis 6 patients received chemotherapy, 3

of them with steroids, one only received steroids

An immune disease was observed in 3 patients (58, 63, and 71 years old) They had respectively lymphopenia with IgG1 and IgG4 deficit, seborrheic pemphigus treated

by steroids, and glomerulonephritis with ANCA treated by AM and steroids

Cystic fibrosis without transplantation was observed in 4 patients, mean age 16.5 years

Three patients aged 74, 76 and 94 years were immunocompetent All of them had

high blood pressure (HBP), one had diabetes

To our knowledge, no patient experienced HIV infection All patients except one were routinely tested for HIV and none had HIV infection The patient who had not been tested had a cutaneous form of nocardiosis, treated in a surgery unit

Clinical and biological characteristics

The main symptoms were: fever (61.7%), cough (35.3%), dyspnea (26.5%), focal neurological defect (20.6%), pain (17.6%), expectoration (11.7%), headache (8.8%), confusion (5.9%), and coma (5.9%)

The main organ localizations of nocardiosis infection were: lung (79.7%), brain (26.5%), cutaneous tissue (26.5%), bones and joints (8.8%), thyroid gland (2.9%), kidney (2.9%), pancreas (2.9%), surrenal glands (2.9%) Bacteremia was found in 26.5% patients.At diagnosis,high CRP (>5.0mg/L) was observed in 92.3% patients (mean 121.0 mg/L), hyperleucocytosis was observed in 53.3% patients, lymphopenia

in 29.2% patientsand 4/10 patients with CD4 counts available had CD4<200/mm3

Microbiological characteristics(table 2: microbiological characteristics)

Nocardia strains were isolated from abscess in 14 patients, BAL in 9, blood culture in

9, sputum in 8 patients

N.farcinica was the main isolated strain (26.5%)

Sensitivity for carbapenem was 95.6%, sensitivity for TMP-SFZ was 61.2%

Outcomes

All patients received antibiotics: 44.1% patients had a double antibiotherapy with TMP-SFZ and carbapenem, 23.5% received a regimen with TMP-SFZ and other

antibiotics,14.7% received a regimen with carbapenem with other antibiotics,17.7%

did not received TMP-SFZ nor carbapenem and were treated according to the

Functional sequellae were observed in 5 patients (14.7%): neurological symptoms after brain abscess (cerebellar syndrome, paresis, speech disorder); dysphonia after thyroid removal, hypoaccousia following aminosidine treatment

In 3 patients, all with cystic fibrosis, the same Nocardia strain was found again in

sputum after treatment of a first episode

Characteristic according to clinical presentations(table 3: characteristics of

patients according to clinical form)

Regarding the clinical presentation and evolution, 4 different clinical forms could be

identified: disseminated form defined by 2 or more organ localizations and/or

bacteriemia, isolated visceral form, bronchial form with respiratory symptoms and no radiological evidence of lung disease, and isolate cutaneous infection

Disseminated form (50.0%)

Disseminated nocardiosis was the main clinical presentation for 17 patients

All presented with an underlying condition: 8 kidney transplantations, one heart transplantation, 5 malignancies, 2 autoimmune diseases and one lymphopenia with IgG1 and IgG4 defect All received immunosuppressive treatments at diagnosis (10 CNI and/or AM and steroids, 2 steroids only, one chemotherapy and steroids, 4

patients received a chemotherapy)

A chest, abdomen and pelvis computed tomography (CAP CT) was performed in 15

patients (88.2%), and a head CT was performed in 14 (82.3%).With this large

radiologic investigation, multiples visceral localizations were found:lung localization

in 15 patients (88.2%), associated with a brain abscess in 7, bacteriemia in

7,multiples extrapulmonary localizations in 5and with a subcutaneous abscess in 4

Only 2 patients with bacteremia had no visceral localization but 1 of them had no brain CT and the other no body-scanner

Mean duration of antibiotic therapy was 34 weeks (8-56), excluding the 2 patients who died quickly Surgery was performed in 9 patients (52.9%)

A cure without sequellae was obtained in 10 patients (58.8%), 5 had neurological

sequellae (29.4%), 2 died from sepsis (11.7%)

Monovisceral form: pulmonary and brain infections (26.5%)

Monovisceral form was the second most common clinical presentation in 9 patients Seven of them were immunocompromised: 3 had lung transplantation, 2 haemopathy, one solid cancer and one livertransplantation Cystic fibrosis was observed in one patient, and one was a 76 years old man with HBP only

Lung localization was observed in 7 patients, 6 were explored with CAP CT associated with head CT in 3 patients, and one with chest and head CT

Localized brain nocardiosis was observed in 2 patients with haemopathy, explored only with head CT and head MRI, without blood culture

Mean duration of antibiotic therapy was 13.6 weeks (2-24).Two patients had surgery for brain abscess

A cure was obtained in 7 patients without sequellae (77.8%), 2 patients (22.2%) died from sepsis (one liver and one lung transplant from multibacterial pneumoniae with

Nocardia spp) A recurrence during the next 24 months was observed in one patient

with cystic fibrosis

Bronchial form (14.7%)

Bronchial form was defined by poor respiratory symptoms, positive sputum for

Nocardiaspp, without radiological evidence of pneumonia It was observed in 5

patients

All patients had a chronic lung disease: cystic fibrosis (n=3), lung transplantation (n=1), and one BMT complicated with GVHD and bronchiolitis obliterans (n=1) Chest X-ray was performed in 4 patients including one with a chest CT; one patienthad no radiological exploration

N.cyriacygeorgica was the main strain (60%).Nocardia spp was always isolated in

sputum and was associated with one or more other pathogens for 4 patients;