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 International Journal of Infectious Diseases 81 (2019) 97–99

Contents lists available at ScienceDirect

International Journal of Infectious Diseases

journal homepage: www.elsevier.com/locate/ijid

Case Report

Granulomatous hepatitis by Nocardia species: An unusual case

Shreya Singh, Yogita Verma, Pooja Pandey, Urvashi B. Singh*
Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India

A R T I C L E I N F O A B S T R A C T

Article history: A case of granulomatous hepatitis due to Nocardia is reported here. The case patient was a 63-year-old
Received 23 August 2018 immunocompetent man who presented with persistent fever, weight loss, and malaise. Radiology
Received in revised form 29 January 2019 suggested an enlarged liver with dense diffuse to multiple tiny micronodular areas of parenchymal
Accepted 29 January 2019
involvement, possibly granulomatous. Liver biopsy showed necrotizing granulomas and anti-
Corresponding Editor: Eskild Petersen, Aar-
hus, Denmark
tuberculosis therapy was initiated, but the patient showed no improvement. A repeat liver biopsy
showed similar histopathology; however PCR for Mycobacterium tuberculosis was negative, while MGIT
960 culture grew filamentous Gram-positive bacilli, acid-fast by 1% H2SO4, identified biochemically as
Keywords:
Pyrexia of unknown origin (PUO)
Nocardia spp. 16S rRNA sequencing confirmed Nocardia spp. A diagnosis of granulomatous hepatitis due
Actinomycete to Nocardia spp. was made. Treatment based on drug sensitivity testing was initiated, resulting in a
Immunocompetent resolution of symptoms. The patient’s history revealed that stray dogs adopted by his family had skin
Disseminated nocardiosis lesions, likely canine distemper (two newborn puppies had died recently). Nocardia is known to co-infect
animals with distemper. This could have been the possible source of a zoonotic infection to the case
patient. Nocardia spp. are seldom reported from sites other than the lungs, skin, or brain; the current case
highlights the involvement of the liver. Due to the granulomatous tissue response, it could represent a
differential diagnosis of tuberculosis in such cases.
© 2019 Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction sonography. Investigations including peripheral smear for malaria

parasites, a malaria antigen test, enteric fever serology, Leptospira
Nocardia is an aerobic actinomycete responsible for localized or serology, retroviral serology, viral hepatitis serology, and Brucella
disseminated infections in animals and humans (reported from the serology were within normal limits, and a peripheral blood film
lungs, brain, and skin). A case of pyrexia of unknown origin (PUO) demonstrated no evidence of toxic granules or atypical cells. Bone
with granulomatous hepatitis caused by Nocardia spp. is reported marrow aspiration with cultures was subsequently performed, the
here. This etiology is not often suspected. With this case report, we results of which were non-contributory.
wish to highlight the diagnostic dilemma faced during the Further investigations were done, including serum and urine
investigation of this case, and how the diagnosis was reached protein electrophoresis, anti-nuclear antibody levels, anti-smooth
and linked to a possible source. muscle antibody levels, and anti-mitochondrial antibody levels,
which were inconclusive. Advanced imaging was subsequently
Case presentation sought with contrast-enhanced computed tomography scanning of
the abdomen. This suggested diffuse liver involvement with
The case patient was a 63-year-old man who presented in multiple tiny micronodular areas, possibly granulomatous. Liver
March 2013 with fever (with evening rise), significant weight loss, biopsy revealed granulomatous hepatitis with bridging fibrosis
and malaise occurring over a period of a few weeks. Physical (Figure 1), suggestive of tuberculosis (TB), and the patient was
examination did not reveal any significant finding. Liver function started on anti-TB therapy with isoniazid, rifampicin, streptomy-
tests showed raised alkaline phosphatase and gamma-glutamyl cin, and ethambutol. This initial biopsy sample could not be
transferase, low albumin, and a low albumin-to-globulin ratio. cultured due to inadequate material and the patient was subjected
Initial evaluation demonstrated sterile blood and urine cultures, to a second liver biopsy after 2 weeks, which corroborated the
normal chest radiography, and an unremarkable abdominal histopathological findings of the first biopsy. The patient failed to
demonstrate a clinical response to the initiated anti-TB treatment.
Retrospective history-taking revealed the presence of stray
* Corresponding author at: Tuberculosis Section, Department of Microbiology, All dogs – a new mother and her puppies – which had been adopted as
India Institute of Medical Sciences, New Delhi, India. pets by the patient’s family. The death of two puppies and

https://doi.org/10.1016/j.ijid.2019.01.046
1201-9712/© 2019 Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
98 S. Singh et al. / International Journal of Infectious Diseases 81 (2019) 97–99

resistant to cefotaxime, cefixime, ceftriaxone, erythromycin, and

tetracycline by disk diffusion, suggesting the organism to be
Nocardia farcinica.
16S rRNA PCR sequencing (Sanger sequencing using an ABI 3130
analyzer) confirmed results consistent with the isolate being
Nocardia spp. (Philip and Böttger, 1998). The sequence was
submitted to GenBank and assigned accession number MH712511.

Treatment

There was a resolution of clinical symptoms following

treatment with intravenous amikacin and co-trimoxazole. The
patient’s condition subsequently improved and he was discharged
from the hospital. After about 2 weeks of treatment the patient
developed ascites probably following hepatic cirrhosis secondary
to diffuse granulomatous hepatitis. By 4 weeks of treatment, the
fever and ascites had subsided, but subsequently, the clinical
course continued to worsen and the patient died due to worsening
cirrhosis.

Figure 1. Biopsy shows acinar disarray. There are several large necrotizing Discussion
epithelioid cell granulomas mainly involving zone 3 and 2. These granulomas
show peripheral epithelioidhistiocytes admixed with neutrophils and central acute
This patient presented with PUO without any immune
inflammatory cells, necrosis and bacterial colonies. There is prominent central to
central bridging necrosis with edema and hepatocyte loss. Portal tracts show suppression. The lack of response to anti-TB therapy in a patient
minimal to mild chronic inflammation. Periportal hepatocytes are viable, with PUO and granulomatous hepatitis should prompt suspicion
uninvolved by the granulomatous process and display mild ballooning degenera- and investigations for further differential diagnoses. In this case,
tion and mild macrovesicular steatosis. ZN staining done for AFB is noncontributory. the treating gastroenterologists were not convinced of Nocardia as
Viral inclusions, fungus or atypical cells are not seen in the submitted biopsy.
the causative pathogen due to the lack of similar published
Impression: Granulomatous Hepatitis with Bridging Necrosis.
evidence. However, the history of companionship of pet dogs with
skin lesions due to distemper, known to become co-infected with
Nocardia (Ribeiro et al., 2008), explained the possible source of the
cutaneous lesions over the mammary glands of the lactating
infection in this case.
mother were thought to be due to canine distemper. Of note,
Infections due to Nocardia are acquired by contact with soil or
Nocardia is known to co-infect animals infected with distemper
inhalation. In nearly 70% of cases, disseminated nocardiosis occurs
virus (Ribeiro et al., 2008). The patient also reported using the
in immunocompromised patients with conditions like post-organ
same bed as that used to house the sick puppies.
transplant, cancer/cancer chemotherapy, lymphoproliferative
syndromes, HIV (CD4 counts <100 cells/ml), systemic lupus
Differential diagnosis
erythematosus (SLE), or prolonged corticosteroid therapy (Sau-
bolle and Sussland, 2003).
Radiological examination was suggestive of granulomatous
Disseminated nocardiosis presents most commonly as a lesion
hepatitis, and liver biopsy revealed granulomatous hepatitis
in the lungs (40%), followed by central nervous system (CNS) (20–
with bridging fibrosis, suggestive of TB. The first biopsy sample
40%). It can present as a deep-seated abscess in virtually any organ.
was not sent for culture. The patient did not respond to the anti-
Case reports reveal a spectrum of presentations, ranging from
TB therapy and was irregular with the treatment. His personal
retroperitoneal abscess, testicular abscess, thyroid abscess, and
history revealed many pet dogs within the family. Two puppies
salivary gland abscess to cardiac tamponade (Vand^me et al., 2001;
had died a few months back and cutaneous lesions over the
de Montmollin et al., 2012; Shetty et al., 2011; Salazar et al., 2013).
mammary glands of the lactating mother led to the suspicion of
Disseminated nocardiosis, solitary pulmonary and CNS lesions,
a possible zoonotic source of infection. To increase the
and single deep-seated abscesses in other organs (salivary gland
sensitivity of the diagnosis, a second liver biopsy was done
abscess, breast abscess, and thyroid abscess) have been reported in
after 2 months and showed similar histopathology findings; this
immunocompetent hosts (Matulionyte et al., 2004).
was also sent for culture and PCR.
Nocardia spp. are seldom seen in sites other than the lungs, skin,
and brain. This report shows that the liver too is another possible
Microbiological investigations
site of infection. Clinicians could confuse this with TB and it is
therefore important to keep an open mind when approaching such
PCR for Mycobacterium tuberculosis was negative (in-house PCR
cases. In addition, this case highlights the possible zoonotic
for the Mpt64 gene) (Singh et al., 2006). MGIT 960 culture tubes
transmission from infected skin lesions in pet dogs.
turned positive, and subculture on blood agar showed a chalky
white, dry adherent growth by the third day. Growth on
MacConkey agar was positive. Lowenstein–Jensen medium Acknowledgements
showed an orange–tan growth by the third day. On Gram staining,
Gram-positive, thin, filamentous, branching bacilli were seen. They We thank the technical staff of the TB Division, Department of
were acid-fast to 1% H2SO4, suggesting Nocardia species. Microbiology, AIIMS, New Delhi, India for their support.
A nitrate reduction test and paraffin bait tests were positive and
the isolate did not hydrolyze 12% gelatin or grow in 0.4% gelatin. Funding
The isolate was sensitive to co-trimoxazole, gentamicin, amikacin,
amoxicillin–clavulanate, imipenem, and levofloxacin and was None.
 S. Singh et al. / International Journal of Infectious Diseases 81 (2019) 97–99 99

Ethical approval Philip K, Böttger EC. Species identification of mycobacteria using rDNA
sequencing. In: Totowa NJ, editor. Methods Mol Biol. New York: Human
Press Inc.; 1998.
The authors declare that ethical approval was not required for Ribeiro MG, Salerno T, Mattos-Guaraldi AL, Camello TC, Langoni H, Siqueira AK.
this study. Nocardiosis: an overview and additional report of 28 cases in cattle and dogs.
Rev Inst Med Trop Sao Paulo 2008;50(3):177–85.
Saubolle MA, Sussland D. Nocardiosis: review of clinical and laboratory experience. J
Conflict of interest Clin Microbiol 2003;41(October (10)):4497–501.
Shetty PV, Kannappan O, Sarma YS. Salivary gland nocardiosis in an immunocom-
The authors report no conflicts of interest. The authors alone are petent patient. Asian J Surg 2011;34(April (2)):99–101.
Salazar MN, Wray D, Denlinger C, Srinivas T, Thomas B, Posadas A.
responsible for the content and writing of the paper. Mediastinal mass and pericardial tamponade in a renal transplant
recipient: a rare case of nocardia infection. Am J Case Rep 2013;14
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