Disseminated BCG Infection ( BCGosis ) After BCG Vaccination

BCG vaccine has excellent safety profile. Disseminated BCG infection, so called BCGosis and death have occurred in few cases, mainly in those with impaired immunity. We are reporting a seven month old infant who developed BCGosis after BCG vaccination. She presented with weight loss, fever, axillary lymphadenopathy and hepato-splenomegaly. She did not respond to standard antitubercular treatment. In the context of increasing number of reported cases of BCGois in HIV era, inoculation of BCG might be postponed in a suspected case of immune-deficiency disease, until it is ruled out. DOI: http://dx.doi.org/10.3126/jnps.v34i1.9679 J Nepal Paediatr Soc 2014;34(1):62-64


Introduction
B CG (Bacilli Calme e-Guérin) vaccine is administered worldwide to prevent severe forms of tuberculosis and is recommended for rou ne use at birth in countries with high tuberculosis prevalence.It has an excellent safety profi le with rare serious complica ons 1 .Side eff ects-most commonly, ulcera on at the vaccina on site and regional lymphadeni s occur in < 1% to 10% of vaccinated individuals 2 .Disseminated BCG infec on, so called BCGosis and death have occurred in 1 to 20 cases per 10 million doses administered, although this problem is restricted to persons with impaired immunity, such as children with severe combined immunodefi ciency disease (SCID), chronic granulomatous disease (CGD) or with human immunodefi ciency virus (HIV) infec on 2,3,4,5,6,7 .We are repor ng an infant admi ed to BP Koirala Ins tute of Health Sciences, Dharan, Nepal, who had systemic BCG infec on (BCGosis) a er BCG vaccina on.

The Case
A seven month age female baby presented to our hospital with history of progressively enlarging swelling at right axillary region with pus discharge for three months, fever for two months and progressive abdominal distension with weight loss for last one month.Child was vaccinated with BCG at 38 days of life.There was no history of contact to adult tuberculosis cases.Birth history was uneven ul and development was op mal.
At the me of admission, the child was emaciated, pale and had an axillary temperature of 100.6°F.The site of BCG vaccina on was indurated and erythematous.A so to fi rm, mobile right axillary lymph node (4x4 cm in size) was present which was discharging scanty amount of pus.On abdominal examina on, there were fi rm hepatomegaly (6 cm below subcostal margin) and fi rm splenomegaly (5 cm below subcostal margin).
Laboratory inves ga ons revealed a leukocyte count of 21,300 (35% lymphocytes) and hemoglobin of 7.5 g/ dl.Erythrocyte sedimenta on rate was 45 mm in 1 st hour.rK 39 test for visceral leishmaniasis and peripheral smear for malaria were nega ve.Ultrasound abdomen showed hepato-splenomegaly with mul ple hypoechoic lesions within This work is licensed under a Creative Commons Attribution 3.0 License.splenic parenchyma and mesenteric lymphadenopathy.Tuberculin test was non-reac ve, microscopic examina on of gastric aspirate was nega ve for acidfast bacilli and Gene Xpert (polymerase chain reac on test for M tuberculosis DNA) was also nega ve.Fine needle aspira on cytology from axillary lymph node showed the presence of acid fast bacilli.An body tests for HIV, Hepa s B, Hepa s C as and VDRL tests were nega ve.When all inves ga ons were completed, the child was already receiving two weeks of empirical an bio c therapy but there was no response.We made diagnosis of disseminated BCG infec on.An tubercular treatment (ATT) with combina on of four drugs (Isoniazid, Rifampin, Ethambutol and Pyrazinamide) was started.On re-assessment a er one month of ATT, there was no improvement in any symptoms and signs.There were progressive enlargements of lymph node, liver and spleen.General condi on was deteriora ng and child was s ll febrile.Because of economic constraints and progressive deteriora on in general condi on despite treatment, parents denied further inves ga on and child was discharged home on ATT.There was no opportunity to evaluate the pa ent for primary immunodefi ciency diseases.

Discussion
The live a enuated Mycobacterium bovis-derived vaccine was fi rst introduced in 1921.Since then billions of doses have been used and it is historically proven to be safe 1 .However, serious complica ons like disseminated BCG infec on, also called BCGosis, rarely do occur.Disseminated BCG infec on is found in 1 to nearly 20 cases per 10 million doses, given a mortality rate of 50% to 80%, based on various studies 2,8 .Although serious complica ons of BCG vaccina on including generalized lymphadeni s and disseminated infec on do occur in immune-competentl hosts, immune-compromised infants and children are at greatest risk of developing BCGosis and most of the reported cases had, either acquired immunodefi ciency like acquired immunodefi ciency syndrome (AIDS) or primary immunodefi ciency like SCID, CGD and other cell-mediated immune defects 3,4,5,6,7,9 .A rise in incidence is seen with higher rates in more recent studies, perhaps owing to AIDS 3,8,10,11 .Disseminated BCG disease has historically been a disease of infants and young children.Most of the reported cases are infants and young children.In a review study of 28 cases by Talbot et al., 82% of the cases occurred in children younger than 3 years old 3 .Disseminated BCG disease occurred in eight children younger than 6-months old and 12 pa ent younger than 12-months old out of 15 cases reported by Rezai et al 7 .Our pa ent also was a 7-month-old female infant.But cases are now occurring also in adults and older children coinfected with human immunodefi ciency virus 3 .Though excep onal, BCGosis have been reported in many immune-competent children also 3,7 .We ruled out the possibility of HIV infec on but unfortunately, we did not have the opportunity and resources to evaluate our child for primary immunodefi ciency.
In the review study of 28 cases by Talbot et al., it was shown that the most common site of dissemina on, established by culture or histological demonstra on of acid-fast bacilli, was lymph node, iden fi ed in 85% of cases.Blood and bone marrow were posi ve for BCG in one third of cases.Other common sites of dissemina on were lungs, liver, spleen, skin and bone.The most commonly reported symptoms were fever, lymphadenopathy and weight loss.Failure to thrive and organomegaly were also common 3 .As we reported in our case, severe axillary lymphadeni s, hepatosplenomegaly and failure to thrive are common clinical features in many other reported cases 6,9 .
Our case did not respond to standard ATT.Response to therapy with standard ATT is generally reported to be poor in BCGosis cases with worst response in immunecompromised pa ents 3,4,6 .However, few cases were seen to respond to standard ATT 3,4 .More promising response have been seen when ATT is combined with interferon-gama in selected cases 7,12 .
There are no sta s cs available in Nepal regarding incidence of BCGosis among vaccinated children.Infants in this country are rou nely BCG-vaccinated, and there are many undiagnosed cases of primary or acquired immunodefi ciency.Many of them are prone to develop this complica on.

Conclusion
It is usually recommended to postpone inocula on of BCG for a few months in suspected cases of primary or acquired immunodefi ciency disease, un l appropriate screening tests exclude this diagnosis and vaccina on should then be performed in those with an intact immune system.In the context of increasing number of HIV aff ected infants in Nepal, implementa on of this recommenda on in Nepal should be evaluated and considered.

Fig 1 :Fig 2 :
Fig 1: Infant with BCGosis showing severe was ng and abdominal distension due to hepatosplenomegaly