Late-onset group B streptococcus infections and severe bronchopulmonary dysplasia in an extremely preterm born infant

Abstract

This case report is about a boy born extremely preterm at gestational age of 24 weeks, with extremely low birth weight, developing severe bronchopulmonary dysplasia and in need of mechanical ventilation for 155 days. He also had five recurrent infections with group B streptococcus (GBS) within 4 months from birth, and his respiratory condition clearly deteriorated with every GBS infection. It was difficult to wean him from mechanical ventilation. Finally he was extubated when he was 7 months old and kept out of mechanical ventilation after receiving high-dose methylprednisolone, given according to international recommendations. After GBS was cultured for the fifth time, he received oral rifampicin along with intravenous penicillin and after this treatment, GBS did not occur again. At the age of 22 months, the boy no longer needed any respiratory support and he was about 6 months late in his neurological development.

Background

Through this case report, we wish to bring out the importance of repeated doses of pulse steroids, in managing a patient with severe bronchopulmonary dysplasia (BPD) from mechanical ventilation after several months, in combination with treatment of five late-onset group B streptococcus (GBS) infections.

BPD is the most common chronic lung disease affecting extremely preterm infants. Its incidence is inversely related to the gestational age.^{1 2} BPD is characterised by disrupted lung development with inhibited alveolar growth and impaired vascular development.^3–5 The pathogenesis of BPD is complex and influenced primarily by immaturity, infections, supplementary oxygen and mechanical ventilation.^6–9 Early weaning from mechanical ventilation with successful extubation may reduce the risk of these complications.¹⁰ However, recurrent infection is associated with increasing risk of reintubation and prolonged periods on mechanical ventilation, increasing the risk of BPD. BPD, intraventricular haemorrhage and retinopathy of prematurity are all thought to be aggravated by bacterial infection causing systemic inflammation.8 9 11 12 GBS is a well-known cause of neonatal sepsis. It is more common in the early neonatal period due to maternal genital tract transmission and less in the late neonatal period due to intestinal colonisation or horizontal transmission.¹³

Case presentation

The case is about a boy born extremely premature at a gestational age of 24 weeks and 2 days with a birth weight of 528 g. The mother was admitted to the hospital since gestational week 20 due to vaginal bleeding and suspicion of premature rupture of membranes. Treatment with corticosteroid for lung maturation was administered twice according to guidelines.

The birth was a spontaneous vaginal delivery (APGAR score 6/1 and 10/5). Based on high oxygen requirement (60%), surfactant was given twice during the first 24 hours. Later, the boy was stable with nasal continuous positive airway pressure (nCPAP) for a week.

See table 1 for an overview of infections with GBS, respiratory support and medical treatment. The reported inflammatory parameter in the table is C reactive protein.

Table 1.

Overview of age in days since birth, GBS infections, cultures and medical treatment, respiratory support and treatment with steroids

Age in days since birth	Infection, bacterial culture and highest CRP (mg/L) (on day)	Treatment of GBS (and other infections with antibiotics)	Respiratory support	Number of days on mechanical ventilation	Treatment with steroids (and other medications for circulatory and respiratory support)
0	-	(Ampicillin and aminoglycoside (intravenous) for 3 days due to premature rupture of membranes and need of surfactant)	nCPAP INSURE for surfactant	–	–
8	GBS in blood culture (day 8) CRP 53 (day 10)	Cephalosporin* (intravenous) and aminoglycoside † (intravenous), change to penicillin (intravenous) for 10 days after verification of culture LP without meningitis	SIPPV nCPAP for 12 hours day 21	20	(Ibuprofen, 10 mg/kg day 1, 5 mg/kg day 2– 5 for closing PDA)
13
20					Dexamethasone, 0.1 mg/kg/day, tapering down daily for 10 days
22	GBS in blood and ET secretion cultures (day 22) CRP 107 (day 22)	Cephalosporin (intravenous) and aminoglycoside (intravenous), change to ampicillin (intravenous) for 2 weeks after verification of culture LP without meningitis
29			nCPAP	–
35					Dexamethasone, 0.1 mg/kg/day, tapering down daily for 10 days
43	GBS in blood culture and cellulitis-adenitis syndrome (day 43) CRP 126 (day 44)	Cephalosporin (intravenous) and aminoglycoside (intravenous), change to penicillin (intravenous) for 3 weeks in combination with aminoglycoside (intravenous) for 2 weeks. LP without meningitis. The mother received 10 days of oral penicillin.	HFOV iNO from day 58 to 66 and 75 to 91	82	–
47					Dexamethasone, 0.1 mg/kg/day, tapering down daily for 13 days
59					(Sildenafil orally until day 369 due to pulmonary hypertension)
62					Dexamethasone, 0.2 mg/kg/day, tapering down daily for 10 days
65		Immunoglobulin, 800 mg/day for 3 days
75	GBS in ET secretion culture (day 75) CRP 60 (day 76)	Cephalosporin (intravenous) and aminoglycoside (intravenous), change to penicillin (intravenous) after positive tracheal culture. Treatment period was 4 weeks (until day 103)			(Dobutamine from day 76 to 94 and dopamine from day 77 to 90). (Sedation with midazolam and fentanil was necessary for shorter periods of time during the period with HFOV and iNO treatment)
104	Negative GBS culture in ETbe secretion	–			–
106 (term age)	GBS in ET secretion culture (day 106) CRP 5.4 (day 114)	Penicillin (intravenous) for 3 weeks supplemented with oral rifampicin added after 1 week and continued for another 2 weeks
125			SIPPV	1
126			nCPAP	–
131	Negative GBS culture in ET secretion and 131) (Viral) infection	(Cepholosporin (intravenous) for 7 days)	SIPPV	9
140		–	nCPAP	–
149	Gastroenteritis CRP<1 (day 149)		SIPPV and tube-CPAP	12	Prednisolone oral 2 mg/kg/dose for 5 days Budesonide inhalation, 2 mg/dose until day 196
161			nCPAP	–
169	Urinary tract infection with enteroccocus faecalis (day 169) CRP 86 (day 169)	(Cepholsporin (intravenous) for 2 days and oral amoxicillin for 7 days)
171			SIPPV and tube-CPAP	2
173			nCPAP	–
174			SIPPV and tube-CPAP	29
203		–	nCPAP	–	–
214			Oxygen need in nCPAP 80%	–	Methylprednisolone, 15 mg/kg/day for 3 days
240			Oxygen need in nCPAP 30%	–	Methylprednisolone, 15 mg/kg/day for 3 days
243	Transferred from level III NICU to level II NICU of another hospital as it was closer to the parents house
302	–	–	HFNC	–	–
307	Discharged home at the chronological age of 10 (corrected age of 6) months and still in need of HFNC
665	No more HFNC at the chronological age of 22 (corrected age of 18) months of age

*Cephalosporine was second-generation (cefuroxime).

†Aminoglycoside was gentamicin.

CRP, C reactive protein; ET, endotracheal tube; GBS, group B streptococcus; HFOV, high-frequency oscillatory ventilation; HFNC, humidified high-flow nasal cannula; iNO, inhaled nitric oxide; INSURE, intubation-surfactant-extubation; LP, lumbar puncture; nCPAP, nasal continuous positive airway pressure; NICU, neonatal intensive care unit; PDA, patent ductus arteriosus; SIPPV, synchronised intermittent positive pressure ventilation.

On day 106, oral rifampicin was added to the penicillin treatment, trying to eradicate GBS from the mucous membranes. After this treatment GBS was not cultured again.

A few days after extubation on day 203, the oxygen requirement rose to 80%, and it was agreed to initiate high-dose methylprednisolone treatment. After initiation of high-dose methylprednisolone, there has been no further need for mechanical ventilation.

The boy was transferred from a level III to II neonatal intensive care unit (NICU) on day 243 and discharged home on day 307.

Investigations

Other clinical and paraclinical investigations not presented are described in detail in table 1.

The mother’s urine was screened for bacteria prebirth, and no GBS was found. The breast milk was examined for bacteria twice (days 26 and 27). No rectal or vaginal swab of the mother was performed. We cultured only coagulase-negative staphylococcus in mother’s milk.

X-ray taken on day 8 showed alterations corresponding to respiratory distress syndrome (RDS). Ongoing X-rays showed increasing signs of BPD (see figure 1).

Figure 1.

X-ray showing lung affected with BPD. BPD, bronchopulmonary dysplasia.

Echocardiography (Echo) showed a patent ductus arteriosus (PDA), which was treated with Ibuprofen for 5 days with treatment initiated on day 13. After 2 weeks of treatment, the PDA remained closed. From day 59, Echo revealed signs of pulmonary hypertension. Echos were performed on a regular basis and it did not show any sign of endocarditis.

On day 43, a sign of an abscess over the left clavicle was observed, and intubation was needed as part of surgical clearing of the abscess. During surgery, no sign of abscess was found, but cellulitis-adenitis syndrome was diagnosed.

On day 58, inhaled NO (iNO) was initiated due to an oxygen demand of 100% in high-pressure ventilation. After iNO administration, it was possible to reduce p-mean from 22 to 10–14 cm H₂O gradually. iNO was reduced within 8 days and it was gradually replaced with sildenafil in treating pulmonary hypertension and the ventilation/perfusion mismatch.

On day 121, the T–B–NK cells were evaluated due to suspicion of immune incompetence, but the result was normal.

On day 139, a bronchoscopy was performed due to recurrent infections and X-rays showing continuous infiltration in the right upper lobe. Normal conditions were found including normal vocal cords and no laryngeal oedema.

On day 192, a high-resolution CT of the chest showed 25%–30% normal lung tissue and several infiltrative changes. Signs of fibrosis and ground glass image compatible with severe BPD were observed (see figure 2).

Figure 2.

CT of thorax showing lung affected with BPD. BPD, bronchopulmonary dysplasia.

Brain ultrasounds were performed several times and were without any intraventricular haemorrhages or periventricular leukomalacia at any time.

There were no signs of retinopathy of prematurity at any time.

All reported positive bacterial cultures were significant otherwise not reported. The endotracheal tube (ET) secretion for cultures was obtained. All bacterial strains that were isolated from the child were checked for sensitivities. No genotyping of any strains of bacteria was unfortunately performed.

Differential diagnosis

Immune deficiency.

Outcome and follow-up

The boy has been without GBS since the last positive culture from ET secretion on day 106. He was discharged from the hospital at the chronological age of 10 months (307 days). He required high-flow nasal cannula (HFNC) for part of the night at home and during upper airway infections until day 665. He was about 6 months delayed in motor development and improving at every monthly check. His fine motor development including speech was better than his gross motor development. A physiotherapist treated the boy during hospital stay and at home after discharge. He received all required vaccinations according to the Danish vaccination programme and monoclonal antibody therapy with palivizumab (Synagis) from October to March after discharge.

Discussion

This case illustrates several interesting issues; primarily, the frequent nature and treatment of late-onset GBS infections and second the outcome of several months of mechanical ventilation, severe BPD and the difficulties associated with weaning a child from mechanical ventilation.

The boy probably hosted the GBS since there were several negative GBS cultures from both the blood and ET secretion while treating with penicillin, and only one negative GBS culture between the fourth and fifth treatment, and this was just 1 day after penicillin was stopped. At the same time GBS is an unusual contaminant in our NICU. Adding rifampicin to the penicillin treatment though seemed to eradicate GBS form the mucous membranes.

To manage GBS infections in the present case, several long-term antibiotic courses were given based on several culture sensitivities. After the third infection, the mother was treated with oral penicillin, even though we were unable to culture any GBS in the mother’s milk. The effect of treating the mother is uncertain. Furthermore, after the third infection, we tried treatment with immunoglobulin based on the fact that recurrent GBS infections have been associated with hypogamma-globulinaemia,¹⁴ though we did not test the boy’s immunoglobulin status beforehand. The fifth positive culture of GBS was treated with a combination of penicillin for 3 weeks and rifampicin for 2 weeks, and subsequently we did not culture GBS again. This is in line with the approach taken in a previous report of successful eradication of GBS infections with penicillin and oral rifampicin.¹⁵ In the present case, we tried prophylactic treatment of the mother with penicillin; however, it might have been more efficient if both the mother and the child had received oral rifampicin, even though we did not prove that the mother was the host of the GBS. We could also speculate if it would have helped changing the ET at the end of an antibiotic treatment, since the ET might as well be colonised with GBS. Prior to the fifth treatment with both penicillin and rifampicin, we cultured GBS from ET secretion but the child did not yet have any signs of infection.

Severe BPD is well known among extremely premature infants, especially if treated with mechanical ventilation for longer periods. We cannot establish which effects these infections had on the boy’s respiratory status, but it was clear that his respiratory condition deteriorated and his BPD worsened with every infection. The third septicaemia resulted in increasing difficulties in ventilation and increased oxygen requirement to 100% and heightened the need for high positive end-expiratory pressure even though this approach involved a high risk of worsening the BPD.¹⁶ Several studies of the administration of postnatal corticosteroids to reduce the risk of BPD in preterm infants have been conducted, and a higher dose has been shown to be more effective compared with a moderate and lower dose of corticosteroids.¹⁷ These studies also show that the use of corticosteroids might be associated with an increased risk of neurodevelopmental impairment, especially if corticosteroids are given early during the postnatal period.¹⁷ Steroids are used to improve lung function by decreasing number of pro-inflammatory and inflammatory cells in severe BPD.¹⁸

Given the boy’s deteriorating respiratory conditions from 2 weeks of age to almost 3 months corrected age, we administered repeated low-dose dexamethasone courses in conformity with local guideline,¹⁹ based on the European consensus guideline treating RDS from 2016,²⁰ even though this approach had well-known risks. According to our guideline, and to decrease the risk of neurological impairment, the patient had to be older than 2 weeks prior to treatment with low-dose dexamethasone. The boy was 20 days old when he was treated for the first time. Parental consent was obtained every time steroids were used in treating the boy after explaining the risk of using steroids. Usually one or sometimes two courses of low-dose dexamethasone help our premature infants from further development of BPD and facilitates extubation, which was challenged in this case probably due to recurrent GBS infections. In our case, the boy’s respiratory condition improved with every corticosteroid course. After the last extubation at 3 months corrected age, high-dose methylprednisolone reduced his oxygen requirement, and because of this improvement, he managed without further need of mechanical ventilation. A tracheotomy was discussed as an option, if methylprednisolone could not have kept him without mechanical ventilation. Instead, he managed to do without any further need of mechanical ventilation and only in need of nCPAP and HFNC until 22 months of age.

Learning points.

• We have learnt that oral rifampicin in combination with intravenous penicillin probably eradicated group B streptococcus (GBS) in the present case with five recurrent GBS infections.

• We have learnt that systemic corticosteroid with high-dose methylprednisolone helped our patient with severe bronchopulmonary dysplasia and need of mechanical ventilation for 155 days. The treatment should probably have been initiated earlier and thereby improved lung function and shortened the time with mechanical ventilation.