Rapidly Progressive Disseminated Bacillus Calmette-Guérin Infection (BCGitis) in a 3-Month-Old Infant Without Immunodeficiency: A Case Report

Introduction

The tuberculosis (TB) vaccine, Bacillus Calmette-Guérin (BCG), is a live attenuated bacilli of Mycobacterium bovis, which recommended for all newborns, unless there are specific contraindications [1]. When BCG vaccine is applied intradermally, it causes an artificial primary infection that aims to develop a specific immune response to control a future bacilli infection [2]. The World Health Organization recommends BCG vaccination in all neonates in those areas with a high prevalence of TB, which includes Brazil and more than 150 countries. Since 1976, all Brazilian newborns have received the vaccine in the maternity ward, and there have been minimal adverse reactions [3]. The incidence of adverse BCG reactions is very low, yet may be underestimated, related to the benignity of most cases [4]. Overall, BCG vaccine-associated adverse reactions occur as a result of vaccine strain modifications, administration techniques, viable bacillary batch load, and, most importantly, host characteristics – primarily immune function. Reactions include fever, subcutaneous abscess, keloids, skin lesions at the vaccination site, and severe lymphadenitis. Osteitis and osteomyelitis are uncommon. The complications and adverse reactions of BCG vaccination have been reported in 310 cases per million vaccinated individuals and include lymphadenitis, persistent ulcer, and remote infection. The rarest complication is disseminated BCG disease, with an incidence of approximately 1.56 to 4.29 cases per million vaccinations, which leads to serious complications and has an overall mortality rate of 60% to 80% [5,6]. Hesseling et al proposed phenotypes to BCG-induced disease based on a revised pediatric classification, designated as: local, regional, distant, or disseminated patterns. The diagnosis can be confirmed by clinical course, dermatological features, pathology, specific polymerase chain reaction (PCR), and spoligotyping [7]. Disseminated (or systemic) BCGitis is an infection caused by BCG that progresses with hematogenous or distant lymphatic spread, causing septicemia and involving the lymph nodes, bones, or systemic organs distant from the vaccine injection site, such as lung involvement, splenomegaly, enteropathy. BCGitis is the most severe adverse effect of the BCG vaccine and can lead to severe sepsis and death if left untreated [8]. When BCGitis affects the ear and parotid gland, it can become even more tragic, due to the risk of deafness, paralysis of the facial nerve, dizziness, meningitis, and invasion of the central nervous system due to proximity to the lateral skull base.

The presentation forms of BCGitis can be recognized in its natural evolution. Non-suppurative BCGitis occurs earlier and usually resolves spontaneously within a few weeks without any sequelae. In some cases, the affected ganglion progressively increases in size and develops suppuration, swelling, and erythema of the underlying skin. Suppurative BCGitis can develop after 2 to 4 months of BCG vaccination and persist for several months. BCGitis occurrence is most commonly secondary to immune deficiency, especially primary immunodeficiency [6,7]. We report a case of a previously healthy patient without detected immune system deficiencies before the diagnosis. In our literature search, we did not find any reported cases of disseminated BCGitis affecting the ear, temporal bone, or parotid gland or simulating a neoplasm in the head and neck.

Case Report

A previously healthy 3-month-old male infant presented with a daily purulent otorrhea unilaterally in the right ear for 1 month, which was refractory to oral antibiotic therapy. This was associated with high fever, irritability, prostration, and weight loss. Even with the administration of broad-spectrum antibiotics, after 1 week of hospitalization, the patient developed progressive growth of an infra-auricular and right retroauricular cervical mass. The mass continued to enlarge and, 2 weeks later, measured approximately 2.5×2.0 cm with phlogosis and a drainage point, in addition to ipsilateral suppurative lymphadenitis. There was associated ipsilateral axillary lymphadenopathy. In the third week, the lesion evolved with an ulcerative-vegetative appearance (Figure 1). Ultrasound examination revealed lymph node enlargement and a lymph node conglomerate at right level II with loss of hilar morphology, measuring 2.6×1.5 cm in its largest axial dimensions. Lymph nodes increased in number, with some enlarged and showing loss of fatty hila at right level IB and bilateral levels II, III, and V, with right-sided predominance. A heterogeneous solid nodule with irregular edges was present in the right retroauricular region, associated with apparent bone erosion of the adjacent mastoid, measuring approximately 2.2×2.1 cm. The right parotid gland was enlarged with heterogeneous echotexture and intraglandular lymph node enlargement (Figure 2). Computed tomography (CT) showed an expansive lesion of the degenerative granulomatous type, with bone involvement, including the tympanic tegmen, and lymph node enlargement (Figure 3). Nuclear magnetic resonance imaging (MRI) showed an expansive and infiltrative lesion in the right cervical region. There was no involvement of the central nervous system (Figure 4).

The patient was hospitalized, and a treatment regimen with large spectrum intravenous antibiotics and corticosteroid was initiated. However, the patient still had fever, abundant purulent secretion, increasing leukocytosis, and elevated inflammatory test results for more than 4 weeks. There were no relevant occurrences of neonatal or family history, except for the maternal report of syphilis treated during the pregnancy of the patient’s 6-year-older brother. There was no parental consanguinity. The patient received BCG and hepatitis B vaccinations at birth. Serology results for HIV, Toxoplasma gondii, Epstein-Barr virus, Paracoccidioides, Histoplasma, Aspergillus, Leishmania, Treponema pallidum, cytomegalovirus, herpes simplex and zoster viruses, rubella, and Bartonella henselae were negative. C-ank, P-ank, anticardiolipin antibodies, rheumatoid factor, antinuclear antibodies, protein and hemoglobin electrophoresis, and all rheumatologic tests were within normal limits. Total lymphocytes, natural killer cells, B and T cells, CD3, CD4, CD8, and CD19 counts were normal, and the CD4/CD8 ratio was unaltered. Serum immunoglobulin levels (IgG, IgA, IgM, and IgE) were within the reference range.

Despite all possible clinical measures and negative laboratory results, the patient’s condition continued to worsen, and we took him to the surgical center in the third week. The incisional biopsy of the lesion showed histiocytosis cells and multiple necrotizing granulomas (Figure 5), with the presence of Fite-Faraco-positive bacilliform structures, identifiable with acid-fast bacilli (Figure 6). M. bovis was isolated in the culture of the abscess secretion. The diagnosis of vaccine reaction to BCG was made, with disseminated infection by M. bovis. The treatment was established with rifampicin, isoniazid, and ethambutol (RIE) for 7 months, based on reports, case series, and literature reviews supporting this regimen as being well tolerated in children. All immunodeficiency screenings showed values within the reference range for serum immunoglobulin and lymphocyte subpopulation levels; the neutrophils oxidation test also showed no changes. The patient became afebrile from the first 3 days of therapy with the RIE regimen and had complete recovery at the end of treatment. MRI at 11 months after the diagnosis showed a complete resolution of the lesions, and lymph nodes disappeared (Figure 7).

During the 3-year follow-up, the child presented normal neurodevelopment and psychomotor function and no other relevant infections or problems with the immune system. We do not find any immunosuppression or comorbidities. The 2 older brothers received the BCG vaccine at birth with no adverse reactions The affected area is well healed eleven months after treatment (Figure 8).

Discussion

The BCG vaccine is derived from M. bovis and can cause BCG vaccine-associated adverse events, especially in those patients with primary immunodeficiency [9]. Although rare, BAC vaccine-associated adverse events include several local and serious systemic complications. Clinical recognition of disseminated BCG infection, as either BCGosis or disseminated BCGitis, is difficult, and there are many reports of diagnoses made only during autopsy [10]. BCGosis is a very devastating complication of BCG immunization in immunocompromised children [11,12]. However, our patient presented without any immunosuppression, even after profound investigation. The most common age of clinical presentation is children younger than 12 months; however, these adverse events can occur from birth to 3 years of age. The rate of disseminated BCGitis incidence is approximately 0.06 to 3.4 cases per million vaccinated individuals and presents a high mortality rate, mainly in immunocompromised patients, with an overall mortality of 60% to 80% [13]. BCGosis mainly occurs in adults with acquired immunodeficiency. It can develop in patients who undergo BCG therapy, including intra-renal or intravesical instillation of BCG for cancer. The most commonly reported immunodeficiencies include combined immunodeficiencies such as HIV infection in the AIDS phase, chronic granulomatous disease, complete DiGeorge syndrome, and Mendelian susceptibility to mycobacterial disease [12,13].

The most common clinical presentation is intermittent fever, unintentional weight loss, systemic or multiorgan abnormalities, and a personal previous history of any immunodeficiency. This is also described as a rare occurrence of disseminated intravascular coagulation [14]. The earliest clinical signs include local erythema that evolves to a progressive edema in the ipsilateral axillary right region (the injection site). This can develop as purulent drainage, generalized lymphadenopathy, mucocutaneous rash, bone involvement, hepatosplenomegaly, and cough. The diagnosis criteria are the existence of systemic symptoms, such as fever, fatigue, weight loss, and malaise, and 2 or more involved areas. The definitive diagnostic criteria are the presence of a BCG vaccination scar with isolation of M. bovis. Therefore, culture and PCR, along with histopathological examination demonstrating granulomatous inflammation and M. bovis, are necessary [15,16].

An important differential diagnosis is scrofuloderma due to M. bovis, which corresponded in the past to 10% of extrapulmonary TB. It usually presents with scrofuloderma, a direct extension of deeper infection to the cutaneous surface, lymphadenopathy, and phlogistic and infectious signs such as fever, mainly in patients with risk factors. To establish the diagnosis, it is necessary to identify M. bovis by PCR or culture. Before the implementation of food safety practices such as pasteurization, M. bovis was heavily associated with scrofula, but now accounts for less than 2% of TB infections in developed countries, such as the United States. Therefore, the pathophysiological mechanism is different, as scrofuloderma is a TB form and not a BCG-induced disease [17].

Primary immunodeficiency diseases are inherited disorders of the immune system that increase the susceptibility to vaccination complications and infections. The most common type of immunodeficiency disorder is severe combined immunodeficiency syndrome, followed by unspecified immunodeficiency (nonspecific changes in CD3, CD4, and CD8 counts on peripheral blood flow cytometry) [17,18]. Basic immune screening to determine underlying immune defects should include serum immunoglobulin levels (IgG, IgA, IgM, and IgE), lymphocyte subsets (CD3+, CD4+, CD8+ T cells; B cells, CD19+; and CD56+ natural killer cells), HIV serology, and neutrophil and interferon-gamma/interleukin-12 oxidation tests. In the present case, the results of these initial complementary tests were normal [19].

In addition, genetic analysis can help detect susceptibility to BCG disorders. The most commonly identified gene alleles in primary immunodeficiency diseases are IL7R, IL2RG, NHEJ1, CYBB, and IL12RB1, with X-linked recessive or autosomal recessive inheritance. Furthermore, additional c.306C and c.270-1G variants of IL2RG, c.87T of CYBB, and deletion of exons 10 and 11 of IL12RB1 have been more rarely reported previously [17,19]. In previous patients, there are very few reports of BCGitis in adults, and most were in the non-disseminated form. Inoculation-site abscesses and erythematous nodules distant from the BCG injection site are exceedingly rare in the immunocompetent population. We did not find any cases of disseminated BCGitis in previous healthy children [20,21].

There is no consensus treatment strategy for disseminated BCGitis, either for medications or duration of treatment. Nevertheless, most reports, case series, and literature reviews report choosing to use the RIE regimen for 6 months. The regimen can be used alone or in combination with corticosteroids, and the infection usually resolves with no sequelae. The sensitivity to isoniazid and rifampicin are satisfied in general BCG vaccine strains currently in use [1–3,21]. This double combination is usually effective and non-inferior, compared with other multidrug regimens containing more than 2 antitubercular drugs. The duration of therapy can vary from months to years, depending on the response and underlying immune defects. M. bovis is intrinsically resistant to pyrazinamide [21,22]. Böhm et al and Cabas et al proposed more extensive studies and a systematic review on the treatment of disseminated BCGiitis. They recommend an anti-TB regimen with isoniazid, rifampicin, pyrazinamide, and ethambutol for 2 months and maintenance therapy with isoniazid and rifampicin for 6 months (rifampicin, isoniazid, and prednisone). Although their studies primarily evaluated BCGiitis after intravesical BCG injection for bladder tumors and in adult patients, we chose to follow their recommendation for our patient because they were the consensus, with the largest number of patients, results, and safety data that we found. Therefore, we used the RIE regimen, as pyrazinamide is not recommended in children, and we completed a total of 7 months of treatment. Throughout treatment, monitoring of clinical and laboratory inflammatory parameters is necessary, even after hospital discharge, as are support and monitoring of the patient’s nutritional and physical status [23,24].

Moxifloxacin might be considered for about 10 months in children with BCGitis [25]. There are many reported cases with intravenous antibiotics, antivirals, and antifungals associated with antitubercular treatment, especially when the diagnosis was not fulfilled or was delayed [26,27]. Our patient was treated for 7 months with RIE, and we stopped only after complete resolution. We considered that the possible adverse effects of ethambutol (mainly impaired vision) were outweighed by the severity of this case. Isoniazid is metabolized in the liver, leading to hepatotoxic metabolites of hydrazine and acetyl hydrazine, with an incidence of 0.6% of hepatotoxicity, hepatocellular necrosis, and steatosis. Rifampicin can cause cholestasis, elevation of conjugated bilirubin, and transient transaminitis, which is often benign. Rarely, it is associated with centrilobular parenchymal necrosis [28,29].

A replacement dose of intravenous immunoglobulin is also important when specific immunosuppression is detected. Alternative vaccinations can be considered when immunosuppressants are previously known or in siblings of patients who had disseminated BCGitis, and include antigen-based vaccines, Mycobacterium tuberculosis (MTB) vaccines, recombinant BCG vaccines, and attenuated MTB vaccines [30,31].

Conclusions

We report an unusually severe course of M. bovis vaccine-associated disease in a previously healthy infant with negative screening for primary immunodeficiency who achieved full recovery with RIE therapy, without sequelae. Clinicians should remain vigilant for disseminated BCGitis, even in immunocompetent patients. Further studies are needed to refine diagnostic and treatment strategies; however, the RIE regimen used in this case was highly effective.