Young girl with recurrent history of mycobacterial disease


Patient presentation

A 9 year old girl of mixed racial ethnicity with a recurrent history of mycobacterial disease presents to a tertiary hospital with a persistently painful, swollen left ankle responding slowly to indicated treatment. She has no other pain but generally feels tired and has a poor appetite.

This case study was kindly provided by Dr Justyna Wojno, from Groote Schuur Hospital, Western Cape

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Three months ago she presented for the first time with an active arthritis in her left ankle, which prevented her from walking. S.aureus was cultured from a tissue biopsy, antibiotic susceptibility testing was done and the patient was put on a course of indicated antibiotics for 6 weeks (two weeks parentral and four weeks oral). Although she appeared to have been compliant on treatment her improvement was minimal.

She continued oral treatment for a further three months after which the joint finally started to settle. The swelling is almost completely resolved and she is able to walk for short distances.

She is also currently on treatment for Mycobacterium avium intracellulare (MAI)
•    Rifampicin 450mg daily
•    Ethambutol 600mg daily
•    Ofloxacin 400mg daily
•    Ethionamide 375mg daily
•    Clarithromycin 250mg bd
•    Pyridoxine 25mg daily
•    Folate 5mg daily
•    Multivitamin 1 tab daily

Past Medical History
Age 6 months: Patient diagnosed with M.tuberculosis infection although her mother was unsure if it was pulmonary or disseminated TB. She completed treatment.

Age 8 years: Patient diagnosed with M.tuberculosis infection which was confirmed as Pulmonary TB by patient’s mother. She completed treatment.

Age 8 years 10 months: Patient presented again with symptoms of Pulmonary TB. She was admitted to hospital and started on treatment for multi-drug resistant –TB (MDR-TB) as she was initially thought to have MDR-TB with this being her third episode of infection. However, culture of a pus swab from a lymph node abscess and a sputum sample revealed the pus swab to be acid fast bacilli (AFB) negative and culture positive for M.tuberculosis and non- M.tuberculosis resembling Mycobacterium avium intracellulare (MAI). The sputum specimen was AFB negative and culture positive for Non- M. tuberculosis (not speciated further). Her therapy was changed to MAI treatment (see above).

Age 9 years: Patient presented with arthritis of the left ankle. A biopsy was taken which cultured S. aureus and the patient received antibiotics for 6 weeks, but the joint hardly responded to treatment. Tissue biopsy from the joint was sent for TB culture and histology. Both results were non-contributory. The histology showed active inflammation with no granuloma formation and the culture was negative for mycobacteria.

Family History
No family members with TB or chronic disease.

Not available

Patient has both parents and 3 siblings. However, she has not been visited by her family as there are social problems and has thus been staying at St Josephs, a home for children with chronic illnesses. She has also been admitted to numerous hospitals and other children’s homes prior to staying at St Josephs.

None known

No additional medication or traditional medicine

Differential Diagnosis

Primary or acquired immunodeficiencies increase the susceptibility to mycobacterial infection, therefore the following should be considered:

  • HIV
  • Diabetes
  • Childhood leukaemia
  • Cystic Fibrosis
  • Severe combined immunodecficiency (SCID)
  • X-linked hyper IgM syndrome
  • Chronic Granulomatous disease
  • Ectodermal dysplasia with immunodeficiency
  • Mendelian susceptibility to mycobacterial disease, especially in tuberculosis-naïve populations where a lack of selection exhibits a greater susceptibility to disease.

The genetic aetiologies include:

  1. IFN-γR1 deficiency
  2. IFN-γR2 deficiency
  3. STAT-1 deficiency
  4. IL-12Rβ1 deficiency
  5. IL-12p40 deficiency
  6. CD40 signaling and NEMO


Patient is a thin, unhappy and unhealthy looking child, walking with an antalgic gait, favouring her right side.

Vital signs
Apyrexial, normal blood pressure and heart rate, normal respiratory rate


  • Pale conjunctiva and noticeable proptosis of left eye, but patient has not reported any eye symptoms or changes.
  • No lymphadenopathy, but scarring from previous cervical lymph node abscess visible
  • Weight- 21.5kg (3rd centile)
  • Height-25th centile

Nil of Note

Respiratory System

  • No abnormalities detected
  • No signs of respiratory distress
  • Normal breath sounds


  • Soft and non-tender
  • No organomegaly
  • Normal bowel sounds

Musculoskeletal system

  • Antalgic gait favouring the right side
  • Left ankle mildly swollen, warm and tender. Full range of motion intact but painful at extremes of movement.
  • No joint crepitations


  • Higher function intact
  • No motor or sensory deficits
  • No cerebellar signs
  • Antalgic gait

The slight proptosis of the left orbit has been assessed by an opthalmologist who postulated that this could be a congenital finding. However, in light of the most recent bone scan results, a local bone lesion of infectious aetiology cannot be excluded.


WBC 21.25 (3.9 – 10.2 x 10ˆ9/l)
Hb 11.7 (11.8 – 14.6 g/dl)
MCV 65.3 (77 -91.5 fl)
MCH 21.6 (25.8 – 31.7 pg)
MCHC 33 (33 – 35 g/dl)
ESR 115
Hypochromic , microcytic anaemia
Neutrophils 67.5 (33 – 55%)
Lymphocytes 25.7 (33 – 50%)
Monocytes, easinophils and basophils Normal
Neutrophils 14.34 (1.45 – 5.2 x 10ˆ9/l)
Lymphocytes 5.46 (1.5 – 4.2 x 10ˆ9/l)

Bone ScanOther parameters normal


Neutrophil oxidative burst test

Lymphocyte Stimulation test
PHA, ConA and Pokeweed responses normal. Protein A response (B cells) is less than 50% of 2 adult controls and Candida (pure protein antigen response) is abnormally low.

Immunoglobulin levels
IgG   19.8  (6-20g/l)
IgA   1.77   (0,8-3g/l)
IgM   2.1    (0,4-1,8g/l)

Sweat test
23 (0-60mmol/l)

Bence-jones proteins in urine

A bone-scan and bone marrow tests were conducted to assess for a disseminated/ chronic cause for the patient’s current features.

Bone scan
A three phase bone scan and spec-CT of the thoracic and lumbar spine showed widespread areas of abnormal uptake/ ‘hot spots’. Areas affected include: skull including the orbits, shoulders, ribs, multiple vertebrae, pelvis, femur and tibia as well as the left ankle.This could possibly indicate disseminated infection such as atypical mycobacterial infection. Patient has not complained of pain in the muskuloskeletal system other than of the left ankle.

Bone marrow
Histology showed hypercellular reactive changes with no evidence of malignancy or granuloma formation.


In the past it was thought that most recurrent TB was due to reactivation as opposed to re-infection. It is now well described that in fact, re-infection is the commonest cause of recurrent TB, especially in areas such as the Western Cape (South Africa) where the prevalence of TB is extremely high.

How then does one assess whether recurrent tuberculosis, in a child, is merely re-infection, or related to an immunodeficiency that may predispose one to invasive, disseminated and/or recurrent infections. Infections due to bacille Calmette-Guerin (BCG) or non-tuberculous mycobacteria (NTM), also known as Mycobacteria other than tuberculosis (MOTT), that are recurrent or disseminated are highly suggestive of impaired immunity. In this case our patient most likely did not receive her BCG vaccination as no infection with M.bovis was isolated.

While BCG immunisation of infants affords moderate protection against extra-pulmonary TB, it can also reveal unsuspected disorders of immune function. Effective containment of live, attenuated BCG bacilli requires intact T-lymphocyte and macrophage function. In the absence of effective host immune function, injected bacilli can proliferate unchecked and spread throughout the body. Unresolved infection at the injection site and its spread to regional lymph nodes can be early indicators of host immunodeficiency, although regional adenopathy alone is relatively common among immunocompetent children. With disseminated infection, the tissues most severely affected are usually the liver, spleen, bone marrow, and lungs. Despite the susceptibility of BCG organisms to most anti-TB medications, the response to treatment is generally poor without immune reconstitution. Massive numbers of organisms are usually evident and concurrent infections with CMV, fungi, and bacteria often occur, adding to the challenges of patient management.

  • HIV
  • Diabetes
  • Childhood leukaemia
  • Bone marrow or organ transplantation
  • Cystic Fibrosis

Primary immunodeficiency (PID) should be considered in a child with recurrent mycobacterial disease. Not all PID’s are associated with a predisposition to mycobacterial infections. One must understand the basis of the immunity necessary to combat mycobacterial organisms to help one understand why this susceptibility occurs. Very briefly, mycobacterial immunity requires a functioning T-cell response with functioning macrophage/IL12/IFN-gamma interactions. Thus there are numerous genes coding for the products responsible for this complex immune interaction. Polymorphisms/mutations in these genes may thus result in immune dysfunction. The following PID’s have an increased susceptibility to mycobacterial disease:

  • Severe combined immunodecficiency: various phenotypic variations of the disease occur but all types are associated with a lack of T-cells with or without B-cell level alterations. These patients can present with local or disseminated post-BCG vaccine infection. Infection with NTM  is also described.
  • X-linked hyper IgM syndrome: a genetic disorder of T-cells. Mutation (in the gene encoding CD154) results in impaired T-cell/ antigen presenting cell interaction. These patients can get disseminated M.tuberculosis or NTM infections.
  • Chronic Granulomatous disease: mutations (in the genes encoding NADPH oxidase subunits) affect the phagocytes’ ability to destroy ingested microorganisms. These patients are predisposed to (among other things) M.tuberculosis and NTM infections.
  • Ectodermal dysplasia with immunodeficiency: mutation in the NEMO gene involved in developmental and immunological pathways that are thus affected downstream. Patients are predisposed to M.tuberculosis and NTM.
  • Mendelian susceptibility to mycobacterial disease: unlike the other PID’s these patients develop mainly severe, disseminated mycobacterial disease. One must remember that the majority of the population have effective innate resistance to mycobacteria and even though almost a third of the world’s population is infected with M.tuberculosis, only 10% will ever develop disease. Is this then a genetic predisposition? Many may argue that social and environmental factors play the most important part, but literature shows that host genetics do play a role. It has been shown that tuberculosis-naïve populations, due to lack of selection, exhibit greater susceptibility to disease.

The genetic aetiology : (Thus far described)

  1. IFN-γR1 deficiency
  2. IFN-γR2 deficiency
  3. STAT-1 deficiency
  4. IL-12Rβ1 deficiency
  5. IL-12p40 deficiency
  6. CD40 signalling and NEMO

It is clear then that there is quite a complex interaction between the host, environment and organism. Therefore immunodeficiency must be considered in a patient with unusual susceptibility to mycobacteria.

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Evaluation – Questions & answers

What is the diagnosis?

Most likely diagnosis is a Mendelian susceptibility to mycobacterial disease. To make a definitive diagnosis genetic studies are required

In the absence of genetic testing what evidence contributes to a diagnosis of Mendelian susceptibility to mycobacterial disease?

Recurrent mycobacterial infections, absent lymphadenopathy and the lack of granulomatous formation as evidenced by “normal” histological findings.

What is the normal immune response to Mycobacteria?

Immune control of mycobacterial infections requires a cell-mediated immune response because mycobacteria are intracellular pathogens. The immune response is initiated by activation of CD4+ T helper cells following phagocytosis of free mycobacteria by dendritic cells. Dendritic cells then produce IL-12 which in turn promotes the differentiation of CD4+ helper T cells to IL-2 and IFN-γ producing Th1 phenotypes. IL-2 is required for activation of CD8+ cytotoxic T Lymphocytes that mediate killing of mycobacteria infected macrophages.

What role does IFN-γ have in the normal immune response to mycobacteria?

INF-γ enhances phagocytosis of free mycobacteria and antigen presentation of mycobacterial proteins to T cells.

Which cells do mycobacteria infect?

Mycobacteria are intracellular pathogens of macrophages, in particular macrophages of lung tissue.

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International Union of Immunological SocietiesUniversity of South AfricaInstitute of Infectious Disease and Molecular MedicineScience Education PrizesElizabeth Glazer Pediatric Aids Foundation