Fatal Pulmonary Mycobacterium Celatum Infection in an Immunocompetent Patient. An Eight-Year Follow-Up of the First Case, a Review of the Literature and a Report of Beta-2 Microglobulin as a Potential Indicator of Disease Severity

doi:10.4236/aid.2013.34038

Paper Menu >>

Journal Menu >>

Advances in Infectious Diseases, 2013, 3, 253-256

Published Online December 2013 (http://www.scirp.org/journal/aid)

http://dx.doi.org/10.4236/aid.2013.34038

Open Access AID

253

Fatal Pulmonary Mycobacterium Celatum Infection in an

Immunocompetent Patient. An Eight-Year Follow-Up of

the First Case, a Review of the Literature and a Report of

Beta-2 Microglobulin as a Potential Indicator of Disease

Severity*

S. Rustscheff, J. Darelid

Department of Internal Medicine, Värnamo General hospital and Department of Infectious diseases, Ryhov County hospital,

Jönköping, Sweden.

Email: [email protected]

Received October 4th, 2013; revised November 3rd, 2013; accepted November 10th, 2013

cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Setting: Swedish cou nty hospital. Objective: Pulmonary M. celatum infection h as been previously described only twice

in an immunocompetent individual with no pre-existing chest disease. We describe the first Swedish case report of un-

usual drug-related complications and review the literature. Discussion: Atypical mycobacteriosis is often difficult to

treat. We describe a fatal case of m celatum pneumonia in a previously healthy patient, unusual side effects encountered

during her treatment and also the report of the utility of beta-2-microglobulin as a way to measure disease activity in my-

cobacterial infections. Conclusions: M. celatum may cause fatal pneumonia in previously healthy individuals. Treating

the disease may be fraught with difficulty and th ere is a risk for very severe side effects, all of which must be weighed

before taking the decision to treat this disease.

Keywords: Mycobacterium Celatum; Immunocompenent

1. Introduction

Mycobacterium celatum was discovered in 1993 [1]. It

belongs to the Runyon group of nonchromogens and has

biochemical characteristics similar to M. xenopii and M.

avium intracellulare. Mycolic acid liquid chromatogram-

phy (HPLC) or 16S rRNA sequencing was often per-

formed for proper identification. However, modern as-

says utilizing reverse hybrid ization is av ailable no wada ys.

It is a pathogen of various animals such as the domestic

ferret [2] and the white-tailed trogon [3] and may also be

found in clinically healthy aqua rium fish [4].

The first human cases described by Tortoli and Pier-

simoni [5] were found among AIDS victims and a grand

total of 28 patients have been reported since 1994. Infec-

tions in immunocompetent patients seem to be exceed-

ingly rare. The first report of a localized lymp hadenitis in

a previously healthy boy, came in 1994 [6] and a second

in a 22-month-old infant was in 2004 [7]. The first case of

pulmonary infection in an immunocompetent individual

was detected post mortem in a patient treated for suspect-

ed tuberculosis [8]. The second case was described from

Maastricht in 1999, where a 61-year-old male was pre-

sented with a history of three years of we ight loss, co ugh,

malaise and had a cavity in the right upper lobe. This

case was also misdiagnosed as M. tuberculosis due to a

false positive AMTD test [9]. The next case described in

Italy was a 63-year-old HIV negative lady who, however,

had suffered from pulmonary tuberculosis at the age of

16 and, in addition, had developed bronchiectases [10].

We would like to describe the first fatal case of m cela-

tum pneumonia in an immunocompetent individual with

no predisposing chest pathology.

*This paper has received support in the form of an unrestricted grant o

four weeks of paid research leave to dr Stefan Rustscheff, a part o

which has been used to write this paper. This paper is deemed not to

need ethical approval from the ethics committee of Linköping Univer-

sity hospital, as it is a retro spective review of a clinical case.

Fatal Pulmonary Mycobacterium Celatum Infection in an Immunocompetent Patient.

An Eight-Year Follow-Up of the First Case, a Review of the Literature and a Report

254

of Beta-2 Microglobulin as a Potential Indicator of Disease Severity

2. Case Report

A 77-year-old unmarried former wet-nurse and ship’s

stewardess was in 2001 referred from her private practi-

tioner to a chest clinic in southern Sweden. She was a

native of Sweden but had lived in the United States for

decades as well. She was a lifelong non-smoker.

She presented with a non-productive cough and 10 kg

weight loss. Her chest X-ray showed extensive interstitial

infiltrates in the right lung, discrete infiltrates in the left,

and a cavitation of the right ap ex lung. A ventricular lav-

age was threefold negative on PCR for M. tuberculosis as

was culture on Löwenstein-Jensens medium and the

BACTEC 460 Radiometric system. Four sputum samples

were negative on direct microscopy and PCR against M.

tuberculosis. Her PPD was nevertheless 15 mm. A bron-

choscopy, a ventricular lavage and a sputum sample in

2002 yielded a NTM species both on Bactec and Löwen-

stein-Jensens medium which was identified as Mycobac-

terium avium-intracellulare by the Accuprobe kit. The

strain unfortunately died before sensitivity tests could be

performed. Nevertheless, ex juvantibus treatment was in-

stituted.

Her initial ESR (sedimentation) was 77. She was put

on Rifampin 450 mg, Isoniazid 300 mg and ethambutol

800 mg and followed. Her cough disappeared but due to

rapidly progressive loss of vision, ethambutol was dis-

continued after 11 months of treatment. A central retinal

vein thrombosis was found to be the cause of the loss of

vision. A new bronchoscopy 2003 yielded a mycobacte-

rium sensitive to clarithromycin, amikacin and ethambu-

tol but resistant to ciprofloxacin and rifampicin. This

turned out to be the first Swedish isolate of M. celatum. It

was classified at Karolinska University using 16s rRNA

sequencing.

A re-bronchoscopy 2004 yielded the same result, now

using gas chromatography at the mycobacterial research

laboratory, Lund University (Kristina Persson, BmA,

pers.comm). The growth of M. celatum was considered

to be a commensal. The patient had been losing weight

constantly since 2001, going from 61 kg to 44 kg. This

was attributed to chewing difficulties due to a concomi-

tant trigeminal neuralgia. Her chest x-ray never showed

resolution of the infiltrates and her ESR rose to 81. No

treatment was instituted.

The patient moved to our area in 2005. She was re-

ferred to us from the first hospital for follow-up. She had

an ESR of 90 and a dry cough. Her chest X-ray in May

2005 showed the same picture as in 2004 with right-sided

perihilar fibrotic infiltrates and volu me loss. A new bron-

chos copy was performed and yielded M. celatum, sensi-

tive to amikacin, ofloxacin, clarithromycin and etham-

butol. The strain was classified through reverse hybridi-

zation by the commercial kit “Genotype CM/AS” (Hain

Diagnostics) at Karolinska University. It was also suc-

cessfully cultured on Löwenstein-Jensens medium and

Bactec. Treatment was now instituted with amikacin 500

mg twice weekly, ethambutol and clarithromycin, 1 g per

diem and moxifloxacin 400 mg for two months, with the

intention to reduce ethambutol to 600 mg and discon-

tinue amikacin thereafter, for a total treatment regime of

at least 18 months.

We followed the patient and noted a reduction in ESR

from 90 to 44 and a weight gain to 50 kg. Unfortunately

in January 2006 the patient suffered another retinal vein

thrombosis in her healthy eye and was now clinically

amaurotic. Ethambutol was discontinued in november

2006 because the patient still had some peripheral vision

left and we did not want to risk it if ethambutol happened

to be the cause of her retinal thromboses. Unfortunately,

this decision soon led to a relapse in her pulmonary dis-

ease in april 2007.

She rose in ESR to 89 and developed new patchy infil-

trates on her chest X-ray. A decision was taken to sup-

plement her treatment with amikacin 500 mg twice

weekly again. 3 months afterwards we saw a resolution

of the infiltrates and a return to previous levels in ESR,

42. She remained culture negative. Her cough disappear-

ed and, in spite of her amaurosis she felt much better

than before institution of treatment for her mycobacterial

disease. We could not rule out that her recurrent retinal

thromboses might be a side effect from ethambutol and

she was kept off this drug. In spring 2008 she unfortu-

nately suffered a relapse, making it necessary for us to

reinstate treatment with ethambutol, moxifloxacin and

amikacin in the same dosag e as previously tolerated. This

time, however, the patient developed severe hearing loss

after having had carbamazepine prescribed by another

source for trigeminal neuralgia. Unfortunately, the hear-

ing loss was only partially reversible and the patient was

now dependent on a hearing aid, as well as being amau-

rotic! All antimycobacterial drugs were discontinued in

february 2009. Her ESR varied between 50 and 94 dur-

ing 2009, while her chest X-ray showed a progressively

floccular subhilar infiltrate with an atelectasis until Sep-

tember, when she was admitted with respiratory insuffi-

ciency and an SaO2 of 83%. This X-ray actually showed

partial resolution of the infiltrates but also oedema and

cardiomegaly. She had a 40 mm Hg right ventricular

pressure on her echocardiography, a creatinine level of

113 mmol/l, normal ultrasoun d examinations of her legs,

a D dimer of 2.69 (limit 0.25) and a ventilation perfusion

scintigraphy showing at least an intermediate likelihood

of pulmonary embolism. Treatment with tinzaparin

20,000 E/ml, 0.7 ml·s·c daily was institu ted for 6 months .

The patient could yet again be discharged without sup-

Open Access AID

Fatal Pulmonary Mycobacterium Celatum Infection in an Immunocompetent Patient.

An Eight-Year Follow-Up of the First Case, a Review of the Literature and a Report 255

of Beta-2 Microglobulin as a Potential Indicator of Disease Severity

plemental oxygen.

In august 2010 the patient returned to us, now again

with a respiratory insufficiency and a fast atrial fibrilla-

tion. She was reinstituted on tinzaparin and also received

loracarbef and furosemide. Sputum samples grew proteus

mirabilis and treatment was changed to ciprofloxacin.

Her ESR was only 32 and her CRP 36. Her x-ray showed

progressive infiltrates in her right lower lobe. Neverthe-

less she regained her respiratory sufficiency and was

discharged on September 13th with an alleviated cough in

order to wait for the results of the mycobacterial samples.

She was found dead in her sleep at her home on Sep-

tember 14th, 2010. Her sister refused an autopsy.

During the whole eight-year period we followed her

beta-2 microglobulin serum levels. She had a reasonable

kidney function for her age, with a creatinine clearance

of 40 - 45 and no other known reasons for an elevated

level of beta-2 microglobulin. Her levels before institu-

tion of treatment were 4.1 mg/l (ref 0.6 - 2.4). Treatment

resulted in a rapid drop to 2.7 mg/l. In april 2007, con-

comitant with her exacerbation, levels rose to 3.8 mg/l.

They then went dow n with treatment and hovered around

2.7 mg/l until autumn 2008, when she had another exac-

erbation and a concomitant rise to 5.4 mg/l. On treatment

levels declined to 2.9 mg/l and have on discontinuation

of all therapy risen again to 3.9 mg/l in summer, 2009.

Unfortunately, no beta-2-microglobulin samples were

measured on her last admission to our ward.

3. Discussion

Atypical mycobacteria may be found as commensals in

the bronchial tree, but a surprising number of them are

pathogens in a true sense. Treatment may be prolonged

and very difficult.

A decision to treat non-tuberculous mycobacteria rests

on repeated cultures of the same Specimen, or culture

positive cases with progressive disease and no other

known cause.

We know that M celatum may be misclassified as M

tuberculosis with the Amplified M tuberculosis direct test

[11]. We have been able to grow M. celatum on three

occasions and the patient has responded to treatment,

relapsed twice after amikacin was withdrawn, improved

on its reinstitution, and, finally, succumbing to the dis-

ease when treatment was withheld. We cannot rule out

that this patient first suffered from a mycobacterium

avium-intracellulare infection but we deem it highly un-

likely that this p athogen would be so easily treated th at it

would disappear after just six months of chemotherapy,

never to return, especially when this patient immediately

afterwards g ot col o ni zed by M. celatum.

4. Conclusions

We deem that it is the first Swedish case of a Mycobacte-

rium celatum infection, the first fatal case in a previously

healthy individual, and th e third case in the world of pul-

monary infection in an immunocompetent patient with no

previous lung disease, confirming that M. celatum is a

true pathogen in man. The PPD test was strong ly positive.

Cultures, direct smears and PCR assays have been nega-

tive for M. tuberculosis. We therefore suggest that the

PPD may cross-react with M. celatum. A negative Quan-

tiferon Go ld test has b een performed in 2009. W e postu-

late that central retinal vein thrombosis might be a rare

side effect of etha mbutol.

Unfortunately, the ototoxic effect of aminoglycosides

is well known and may occur more frequently in the eld-

erly, when treatment is prolonged and when other oto-

toxic drugs are added. We therefore advise the utmost

caution when adding potentially ototoxic and/or nephro-

genic drugs to an aminoglycoside-containing regimen,

even if the aminoglycoside is given in a low total weekly

dose. We would also like to point out the dangers of

withholding treatment altogether in these infection s .

Finally, we would like to draw attention to beta-2 mi-

croglobulin, which is said to be synthetised in granulo-

mata. There is an excellent paper published on beta-2 mi-

croglobulin levels in tuberculosis p atients [12]. We tenta-

tively postulate that this test could be of potential value

in monitoring the course of non-tuberculous mycobacte-

rial diseases.

REFERENCES

[1] W. R. Butler, S. P. O’Connor, M. A. Yakrus, R. W.

Smithwick, B. B. Plikay tis, C. W. Moss et al., “Mycobac-

terium Celatum sp.nov,” International Journal of Syste-

matic Bacteriology, Vol. 43, No. 3, 1993, pp. 539-548.

http://dx.doi.org/10.1099/00207713-43-3-539

[2] M. Valheim, B. Djönne, R. Heiene and D. A. Caugant,

“Disseminated Mycobacterium Celatum (Type 3) Infec-

tion in a Domestic Ferret Mustela Putorius Furo),” Vet-

erinary Pathology, Vol. 38, No. 4, 2001, pp. 460-463.

http://dx.doi.org/10.1354/vp.38-4-460

[3] M. F. Bertelsen, C. Gröndahl and S. B. Giese, “Dissemi-

nated Mycobacterium Celatum Infection in a White-Tail-

ed Trogon (Trogon Viridis),” Avian Pathology, Vol. 35,

No. 4, 2006, pp. 316-319.

http://dx.doi.org/10.1080/03079450600821133

[4] V. Beran, L. Matlova, L. Dvorska, P. Svastova and I. Pa-

vlik, “Distribution of Mycobacteria in Clinically Healthy

Ornamental Fish and Their Aquarian Environment,”

Journal of Fish Diseases, Vol. 29, No. 7, 2006, pp. 383-

393. http://dx.doi.org/10.1111/j.1365-2761.2006.00729.x

[5] C. Piersimoni, E. Tortoli, F. de Lalla, D. Nista, D. Donato,

Open Access AID

Fatal Pulmonary Mycobacterium Celatum Infection in an Immunocompetent Patient.

An Eight-Year Follow-Up of the First Case, a Review of the Literature and a Report

of Beta-2 Microglobulin as a Potential Indicator of Disease Severity

Open Access AID

256

S. Bornigia, et al., “Isolation of Mycobacterium Celatum

from Patients Infected with Human Immunodeficiency

Virus,” Clinical Infectious Diseases, Vol. 24, No. 2, 1997,

pp. 144-147.

[6] G. Haase, H. Skopnik, S. Bätge and E. C. Böttger, “Cer-

vical Lymphadenitis Caused by Mycobacterium Cela-

tum,” Lancet, Vol. 344, No. 8928, 1994, pp. 1020-1021.

http://dx.doi.org/10.1016/S0140-6736(94)91680-2

[7] D. C. Christiansen, G. D. Roberts and R. Patel, “Myco-

bacterium Celatum, an Emerging Pathogen and Cause of

False Positive Amplified Mycobacterium Tuberculosis

Direct Test,” Diagnostic Microbiology and Infectious Di-

sease, Vol. 49, No. 1, 2004, pp. 19-24.

[8] I. Bux-Gewehr, H. Hagen, S. Ruesch-Gerdes and G.

Feurle, “Fatal Pulmonary Infection with Mycobacterium

Celatum in an Immunocompetent Patient,” Journal of

Clinical Microbiology, Vol. 36, No. 2, 1998, pp. 587-588.

[9] J. H. T. Tjhie, A. F. van Belle, M. Dessens-Kroon and D.

van Solingen, “Misidentification and Diagnostic Delay

Caused by a False-Positive Amplified Mycobacterium Tu-

berculosis Direct Test in an Immunocompetent Patient

with a Mycobacterium Celatum Infection,” Journal of

Clinical Microbiology, Vol. 39, No. 6, 2001, pp. 2311-

2312.

http://dx.doi.org/10.1128/JCM.39.6.2311-2312.2001

[10] C. Piersimoni, P. G. Zitti, D. Nista and S. Bornigia, “My-

cobacterium Celatum Pulmonary Infection in the Immu-

nocompetent: Case Report and Review,” Emerging Infec-

tious Diseases Journal, Vol. 9, No. 3, 2003, pp. 339-342.

[11] D. Christiansen, G. Roberts and R. Patel, “Mycobacte-

rium Celatum, an Emerging Pathogen and Cause of False

Positive Amplified Mycobacterium Tuberculosis Direct

Test,”

[12] J. Collazos, E. Martinez and J. Mayo, “Evolution of Se-

rum Beta-2 Microglobulin Concentrations during Treat-

ment of Tuberculosis Patients,” Scandinavian Journal of

Infectious Diseases, Vol. 31, No. 3, 1999, pp. 265-267.

http://dx.doi.org/10.1080/00365549950163554