**4. Clinical presentation, classification**

Depending on the time of manifestation of infection neonatal pneumonia may be classified as early onset pneumonia (within the first 3 or 7 days of life, mostly within 48 hours), or late onset pneumonia (within 4 and 28 days of life). Congenital or intrauterine pneumonia can be considered a variant of early onset pneumonia (2). Other classifications refer to the underlying pathogen, like bacterial or viral pneumonia or the pattern of lung infiltrates (e.g. interstitial pneumonia) on chest radiographs. Clinical signs are unspecific and present as respiratory distress of various degree, suspicious appearing tracheal aspirates, cough, apnea, high or low temperature, poor feeding, abdominal distension, and lethargy. Tachypnea is a predominant clinical sign, present in 60-89 % of cases (2). Persistent fever is rather unusual, but has been reported in neonates with viral pneumonia (10). The radiographical appearance may also vary (11), showing reticulogranular-nodular infiltrates, and bilateral streaky or hazy lungs. As small bronchioli tend to collapse there may be compensatory hyperaeration in areas free of pneumonial infiltration. In addition there may be pleural effusions and/or pneumatocele formation in more complicated cases. Alveolar patterns with coarse, patchy parenchymal infiltrates, consolidation, and diffuse granularity are more typical for bacterial infections while parahilar streakiness, diffuse hazy lungs or reticulo-nodularity are more common in viral disease. The differential diagnoses to be considered on initial presentation are mainly surfactant deficiency syndrome and transient tachypnoe of the newborn, in addition meconium aspiration syndrome (MAS), pulmonary hemorrhage, pulmonary edema, primary pulmonary lymphangiectasis or pulmonary lymphangiomatosis, congestive heart failure (11,12) and Wilson-Mikity-syndrome (13). Additional investigations like echocardiography, high-resolution computed tomography, further laboratory studies, and in rare cases lung biopsy are helpful in the diagnostic work up.

#### **5. Diagnosis**

20 Neonatal Bacterial Infection

**3. Pathogenesis** 

(2, 8).

up.

**4. Clinical presentation, classification** 

onset pneumonia are gram-negative bacilli such as E coli or Klebsiella spp.(8). Frequently bacterial pathogens found in early and late onset sepsis/pneumonia are listed in Table 1.

Pneumonia may be acquired by intrauterine (e.g. transplacental hematogenous, ascending from birth canal), intrapartum (e.g aspiration) or postnatal routes (e.g. hematogenous, environmental). The pathogens include mainly bacteria, followed by viruses and fungi which induce an inflammatory pulmonary condition (1,8). This may cause epithelial injury to the airways, leakage of proteinaceous fluid into the alveoli and interstitium, leading to surfactant deficiency or dysfunction. Data from a German study (9) suggest that respiratory insufficiency in pneumonia is most likely caused by inhibition of surface-tension-lowering properties of surfactant rather than by surfactant deficiency. Important predisposing factors in the evolution of pneumonia are immaturity, low birth weight, premature rupture of membranes, chorioamnionitis and factors associated with prolonged neonatal intensive care

Depending on the time of manifestation of infection neonatal pneumonia may be classified as early onset pneumonia (within the first 3 or 7 days of life, mostly within 48 hours), or late onset pneumonia (within 4 and 28 days of life). Congenital or intrauterine pneumonia can be considered a variant of early onset pneumonia (2). Other classifications refer to the underlying pathogen, like bacterial or viral pneumonia or the pattern of lung infiltrates (e.g. interstitial pneumonia) on chest radiographs. Clinical signs are unspecific and present as respiratory distress of various degree, suspicious appearing tracheal aspirates, cough, apnea, high or low temperature, poor feeding, abdominal distension, and lethargy. Tachypnea is a predominant clinical sign, present in 60-89 % of cases (2). Persistent fever is rather unusual, but has been reported in neonates with viral pneumonia (10). The radiographical appearance may also vary (11), showing reticulogranular-nodular infiltrates, and bilateral streaky or hazy lungs. As small bronchioli tend to collapse there may be compensatory hyperaeration in areas free of pneumonial infiltration. In addition there may be pleural effusions and/or pneumatocele formation in more complicated cases. Alveolar patterns with coarse, patchy parenchymal infiltrates, consolidation, and diffuse granularity are more typical for bacterial infections while parahilar streakiness, diffuse hazy lungs or reticulo-nodularity are more common in viral disease. The differential diagnoses to be considered on initial presentation are mainly surfactant deficiency syndrome and transient tachypnoe of the newborn, in addition meconium aspiration syndrome (MAS), pulmonary hemorrhage, pulmonary edema, primary pulmonary lymphangiectasis or pulmonary lymphangiomatosis, congestive heart failure (11,12) and Wilson-Mikity-syndrome (13). Additional investigations like echocardiography, high-resolution computed tomography, further laboratory studies, and in rare cases lung biopsy are helpful in the diagnostic work The clinical diagnosis of pneumonia is challenging and may not always be correct (over- or underestimated). Early tracheal aspirate cultures obtained within the first 8 to 12 hours of age may help in diagnosing congenital pneumonia (14,15), especially in certain clinical conditions, including maternal fever, clinical chorioamnionitis and leukopenia. But even a positive blood culture or proven airway colonization do not necessarily correlate with the clinical picture of sepsis or pneumonia (16). In the clinical routine pneumonia is diagnosed based on a combination of perinatal risk factors, signs of neonatal respiratory distress, positive laboratory studies, radiological signs and a typical clinical course. Some clinical scenarios are more or less suspicious **.** For example VAP, reported to be responsible for up to one third of all nosocomial infections, may be suspected two or more days after the initiation of mechanical ventilation when new or persistent infiltrates are noticed in 2 or more chest radiographs (5). Additional definition criteria developed by the Centers for disease control and prevention (17) include an increase in oxygen and ventilator requirements and at least three of the following signs and symptoms: temperature instability, wheezing, tachypnea, cough, abnormal heart rate, change in respiratory secretions, and abnormal peripheral white blood count. The most common organisms in VAP in extremely preterm infants have been shown to be Staphylococcus aureus and especially gram-negative organisms like Pseudomonas aeruginosa , Enterobacter spp. and Klebsiella spp. (18). Pneumonia caused by Ureaplasma species, Eubacteria mainly colonizing the mucosal surface of the respiratory and urogenital tract, may be diagnosed by direct isolation of the organism from endotracheal aspirates using culture or PCR-techniques, by typical chest-x-ray patterns showing disseminated, patchy infiltrates bilaterally with progression to cystic dysplasia, and elevated inflammatory serum-parameters like CRP or an increased white cell count (19,20,21). An organism frequently associated with early onset pneumonia is Group B Streptococcus. The clinical manifestation occurs usually within 6 of 8 hours of life and can initially mimic surfactant deficiency syndrome (16, 22).

### **6. Treatment, prevention**

As pneumonia is often associated with or non distinguishable from bacterial sepsis initial therapy at the NICU includes broad spectrum intravenous antibiotics according to local protocols. In our unit we start with a combination of ampicillin and a second generation cephalosporine. Although there is no evidence from randomized controlled trials that any antibiotic regime is superior for suspected early onset neonatal sepsis (23), the WHO recommends as first line treatment ampicillin plus gentamycin (24). In cases where we detect pathogens in blood, or in endotracheal aspirates we treat according to susceptibility from antibiogram results. A problem which is increasing worldwide in NICU´s is the occurrence of multidrug resistant pathogens, mainly gram-negative bacilli (25). As an alternative to systemic treatment aerosolized antibiotics like colistin have been used successfully in patients with VAP caused by multidrug resistant gram negative bacteria (26, 27). In patients where we suspect or diagnose an U infection we initiate treatment with intravenous clarithromycin (10mg/kg/day), a macrolid antibiotic. In a recently published randomized controlled placebo single-center study clarithromycin treatment resulted in

eradication of Uu in 68,5 % of the patients and a significantly lower incidence of BPD (2.9% vs. 36.4%) in preterm infants weighing between 750 to 1250 g (28). Azithromycin, another macrolid antibiotic, which has good inhibitory activity against Ureaplasma in in-vitro studies, may also be beneficial for BPD prevention in Ureaplasma colonized/infected preterm infants, especially when used early and for longer duration (29). In general the clinical and microbiological effectiveness of macrolid antibiotics, the most commonly used in the literature being erythromycin, has not yet been shown in adequately powered randomized controlled clinical trials (30). Recommendations for the duration of antibiotic therapy in proven neonatal pneumonia range from 10 to 21 days (8). Surfactant therapy may be beneficial in selected patients by mechanisms improving lung function and decreasing bacterial growth, but may require repeated doses (22, 31,32). However, in a recently published meta- analysis in patients > 35 weeks gestation with proven or suspected pneumonia with onset during the first 28 days of life there was no evidence of a significant effect on the primary outcome death, time to resolution of pneumonia, BPD, pneumothorax and pulmonary hemorrhage (33). There are still open questions related to the surfactant preparation, dosage, optimal treatment frequency, number of doses and patient selection. Severe cases of pneumonia with respiratory insufficiency not responding to conventional therapy may occasionally be candidates for ECMO (34, 35). Preventative measures to be considered include maternal infection control in the prenatal period, prenatal screening and prophylaxis for streptococcal colonization (36), preference of non-or minimal invasive procedures in the neonatal period like respiratory support without intubation (37), immunoprophylaxis against RSV-infection, and general infection control measures in the neonatal unit to reduce the incidence and transmission of health-care-associated infections, the most important being hand hygiene (38,39,40). Preventive strategies that may have a great impact are maternal and infant vaccination programs, as has been already shown in developing countries e.g for pneumococcal polysaccharide vaccines (41).

Neonatal Pneumonia 23

After good primary transition, the infant developed clinical signs of respiratory distress with oxygen dependency and respiratory acidosis (6 hours post partum). After initiation of our standard broad spectrum antibiotic therapy the infant was transferred to our NICU. A septic workup showed leukopenia of 2.70 G/L, a left shift in the white cell count (immature/total neutrophils (I/T) 0,33), markedly elevated procalcitonin (303 ng/mL) and interleukin-6 (IL-6 > 400 pg/L) levels, but normal CRP values, and a positive urinary group B streptococcus testing. Blood cultures and tracheal aspirates were negative. Radiographics showed bilateral reticulogranular patterns compatible with the diagnosis of RDS (Figure 1). The patient was first placed on nasal CPAP but had to be intubated and ventilated mechanically due to respiratory deterioration with an increasing oxygen demand up to an FiO2 of 1,0 and persistent respiratory acidosis. Surfactant therapy showed no sufficient response. Inotropic support was necessary in case of arterial hypotension. Following inhaled nitric oxide therapy a decrease in oxygen requirement from 100 to 50 % was achieved over the following 48 hours, indicative of secondary pulmonary hypertension. On day 5 of life the clinical course was complicated by formation of a large left sided pneumatocele (Figure 2) and a consecutive symptomatic tension pneumothorax (Figure 3), which was successfully treated by insertion of a chest drain. On day 11 of life the patient was extubated, but the chest drain had to be left in situ for 3 ½ weeks due to recurrent air leaks. Laboratory parameters normalized within a week by our standard antibiotic regime. On day 37 of life

**Figure 1.** Bilateral reticulogranular lung pattern in Group B Streptococcus pneumonia mimicking RDS

the neonate had recovered and was discharged home.

(Case 1)


g +/- = gram-positive/negative

\* based on DNA-analysis

**Table 1.** Frequently found bacterial organisms in early and late onset neonatal sepsis and pneumonia

#### **Case 1**

A male neonate was born at 42 weeks gestational age to a multiparous healthy mother following spontaneous labor in an external hospital. The membranes ruptured 3 hours before delivery. There was no prenatal maternal screening for groub B streptococci disease. After good primary transition, the infant developed clinical signs of respiratory distress with oxygen dependency and respiratory acidosis (6 hours post partum). After initiation of our standard broad spectrum antibiotic therapy the infant was transferred to our NICU. A septic workup showed leukopenia of 2.70 G/L, a left shift in the white cell count (immature/total neutrophils (I/T) 0,33), markedly elevated procalcitonin (303 ng/mL) and interleukin-6 (IL-6 > 400 pg/L) levels, but normal CRP values, and a positive urinary group B streptococcus testing. Blood cultures and tracheal aspirates were negative. Radiographics showed bilateral reticulogranular patterns compatible with the diagnosis of RDS (Figure 1). The patient was first placed on nasal CPAP but had to be intubated and ventilated mechanically due to respiratory deterioration with an increasing oxygen demand up to an FiO2 of 1,0 and persistent respiratory acidosis. Surfactant therapy showed no sufficient response. Inotropic support was necessary in case of arterial hypotension. Following inhaled nitric oxide therapy a decrease in oxygen requirement from 100 to 50 % was achieved over the following 48 hours, indicative of secondary pulmonary hypertension. On day 5 of life the clinical course was complicated by formation of a large left sided pneumatocele (Figure 2) and a consecutive symptomatic tension pneumothorax (Figure 3), which was successfully treated by insertion of a chest drain. On day 11 of life the patient was extubated, but the chest drain had to be left in situ for 3 ½ weeks due to recurrent air leaks. Laboratory parameters normalized within a week by our standard antibiotic regime. On day 37 of life the neonate had recovered and was discharged home.

22 Neonatal Bacterial Infection

Enterococcus (g +)

g +/- = gram-positive/negative \* based on DNA-analysis

**Case 1** 

Ureaplasma urealyticum (g+)\*

eradication of Uu in 68,5 % of the patients and a significantly lower incidence of BPD (2.9% vs. 36.4%) in preterm infants weighing between 750 to 1250 g (28). Azithromycin, another macrolid antibiotic, which has good inhibitory activity against Ureaplasma in in-vitro studies, may also be beneficial for BPD prevention in Ureaplasma colonized/infected preterm infants, especially when used early and for longer duration (29). In general the clinical and microbiological effectiveness of macrolid antibiotics, the most commonly used in the literature being erythromycin, has not yet been shown in adequately powered randomized controlled clinical trials (30). Recommendations for the duration of antibiotic therapy in proven neonatal pneumonia range from 10 to 21 days (8). Surfactant therapy may be beneficial in selected patients by mechanisms improving lung function and decreasing bacterial growth, but may require repeated doses (22, 31,32). However, in a recently published meta- analysis in patients > 35 weeks gestation with proven or suspected pneumonia with onset during the first 28 days of life there was no evidence of a significant effect on the primary outcome death, time to resolution of pneumonia, BPD, pneumothorax and pulmonary hemorrhage (33). There are still open questions related to the surfactant preparation, dosage, optimal treatment frequency, number of doses and patient selection. Severe cases of pneumonia with respiratory insufficiency not responding to conventional therapy may occasionally be candidates for ECMO (34, 35). Preventative measures to be considered include maternal infection control in the prenatal period, prenatal screening and prophylaxis for streptococcal colonization (36), preference of non-or minimal invasive procedures in the neonatal period like respiratory support without intubation (37), immunoprophylaxis against RSV-infection, and general infection control measures in the neonatal unit to reduce the incidence and transmission of health-care-associated infections, the most important being hand hygiene (38,39,40). Preventive strategies that may have a great impact are maternal and infant vaccination programs, as has been already shown in

developing countries e.g for pneumococcal polysaccharide vaccines (41).

Escherichea coli (g-) Staphylococcus epidermidis (g+) Staphylococcus aureus (g+) Klebsiella-Enterobacter-species (g-) Listeria monocytogenes (g+) Pseudomonas aeruginosa (g-)

**Table 1.** Frequently found bacterial organisms in early and late onset neonatal sepsis and pneumonia

A male neonate was born at 42 weeks gestational age to a multiparous healthy mother following spontaneous labor in an external hospital. The membranes ruptured 3 hours before delivery. There was no prenatal maternal screening for groub B streptococci disease.

**Early onset (< =7 days) Late onset (> 7 days)** Group B Streptococcus (g +) Escherichia coli (g-)

**Figure 1.** Bilateral reticulogranular lung pattern in Group B Streptococcus pneumonia mimicking RDS (Case 1)

Neonatal Pneumonia 25

A female infant was delivered by vacuum extraction at 37+4 weeks gestational age to a multiparous mother after premature rupture of membranes, meconium stained amniotic fluid and pathological cardiotocogram. Maternal vaginal swabs were tested negative for Group B Streptococcus. Apgar scores and umbilical artery pH were within the normal range. About 12 hours after birth the neonate showed signs of respiratory distress with tachypnea, grunting and an oxygen demand of FiO2 >0,3. He was intubated and transferred to our NICU. A chest radiograph on admission showed bilateral streaky infiltrates (Figure 4). On day 2 an elevated CRP of 100mg/L, in combination with the findings on chest radiographs and the clinical signs were highly suspicious for the diagnosis of early onset neonatal pneumonia. In the yellowish tracheal aspirates Listeria monocytogenes were detected. The asymptomatic mother was tested negative for Listeria infection in stool and u r i n e p r o b e s . O n c l o s e r q u e s t i o n i n g t h e m o t h e r r e m e m b e r e d h a v i n g

**Figure 4.** Bilateral,streaky and nodular infiltrates in Listeria pneumonia (Case 2)

**Case 2** 

**Figure 2.** Pneumatocele formation on the leftside and streaky-granular infiltrates in Group B Streptococcus pneumonia (Case 1)

**Figure 3.** Leftsided tension pneumothorax complicating Group B Streptococcus pneumonia (Case 1)

## **Case 2**

24 Neonatal Bacterial Infection

Streptococcus pneumonia (Case 1)

**Figure 2.** Pneumatocele formation on the leftside and streaky-granular infiltrates in Group B

**Figure 3.** Leftsided tension pneumothorax complicating Group B Streptococcus pneumonia (Case 1)

A female infant was delivered by vacuum extraction at 37+4 weeks gestational age to a multiparous mother after premature rupture of membranes, meconium stained amniotic fluid and pathological cardiotocogram. Maternal vaginal swabs were tested negative for Group B Streptococcus. Apgar scores and umbilical artery pH were within the normal range. About 12 hours after birth the neonate showed signs of respiratory distress with tachypnea, grunting and an oxygen demand of FiO2 >0,3. He was intubated and transferred to our NICU. A chest radiograph on admission showed bilateral streaky infiltrates (Figure 4). On day 2 an elevated CRP of 100mg/L, in combination with the findings on chest radiographs and the clinical signs were highly suspicious for the diagnosis of early onset neonatal pneumonia. In the yellowish tracheal aspirates Listeria monocytogenes were detected. The asymptomatic mother was tested negative for Listeria infection in stool and u r i n e p r o b e s . O n c l o s e r q u e s t i o n i n g t h e m o t h e r r e m e m b e r e d h a v i n g

**Figure 4.** Bilateral,streaky and nodular infiltrates in Listeria pneumonia (Case 2)

developed gastrointestinal symptoms with diarrhea 2 weeks prior to birth after having eaten some cheese made from unpasteurized milk from a local food store. This led us to assume that the pregnant mother had most likely infected the fetus following ingestion of the bacterium, which had then crossed intestinal cells into the bloodstream and passed the placenta (42,43). After initiation of our standard antibiotic therapy the infant recovered quickly and was extubated on day 4 of life. Antibiotics were given for a total of 14 days. The child had a full recovery.

Neonatal Pneumonia 27

antibiotics. The preterm infant showed clinical and radiological signs of RDS and was intubated 15 minutes after birth. Standard broad spectrum antibiotics were started prophylactically but terminated after 3 days when daily white cell counts and CRP levels revealed no signs of infection. The patient was extubated on day 4 of life and placed on nasal CPAP. On day 6 of life the baby appeared septic with new onset of apneas, skin pallor, poor peripheral perfusion, metabolic acidosis and neurological signs like increased muscle tone and extreme irritability. Due to recurrent apneas despite caffeine therapy the infant had to be reintubated. The septic work up confirmed the clinical diagnosis of sepsis. Enterobacter cloacae, ESBL positive, was found in the blood culture, liquor cerebrospinalis and tracheal aspirate. Peripheral blood count showed leukocytosis, I/T ratio of 0,54, thrombocytopenia of 38 G/l, and elevated CRP values of 68,4 rising to a maximum of > 200 mg/L. Chest radiographs revealed new parenchymal changes compatible with the diagnosis of late onset bacterial pneumonia (Figure 5). The antibiotic regime was changed to meropenem and teicoplanin. As a further complication of sepsis the patient developed transient renal failure and an intraventricular hemorrhage with consecutive hydrocephalus, which was finally treated by insertion of a ventriculo-peritoneal shunt. After a long complicated neonatal period the patient was finally discharged from the hospital at an age

A female infant was born at 24+3 weeks gestational age by vaginal delivery after the mother had been admitted to our hospital 1 hour prior to delivery with abdominal pain and onset of labors. The neonate developed RDS soon after birth which led to intubation, surfactant application and mechanical ventilation. Broad spectrum antibiotic therapy was started in case of suspected early onset sepsis. Initial laboratory revealed leukocytosis of 52.00 G/L, increased IL-6 (29,2 pg/ml) but normal CRP values. The chest radiograph on admission was typical for mild RDS but the lung pattern worsened during the first 2 weeks of life showing disseminated streaky-patchy infiltrates and partly cystic changes (Figure 6 and 7), accompanied by an increase in ventilatory requirements suggestive of early BPD changes. Therefore a strategy of moderate early BPD-prevention (48) with a one week course of intravenous steroids (hydrocortisone) was started. Results from routine tracheal aspirate screening for Ureaplasma infection taken during the second day on mechanical ventilation revealed a positive culture test (106) for Uu. In addition the placenta histology showed signs of chorioamnionitis. Under the assumption of early onset ureaplasma pneumonia/ pneumonitis we commenced oral macrolid therapy with clarithromycin (10mg/kg), beginning on day 6 of life for a total of 14 days. A repeat ureaplasma culture taken during treatment was negative. Mechanical ventilation continued for 18 days followed by a prolonged period of NCPAP lasting 7 weeks. Oxygen dependency for more than 8 weeks but not at a corrected gestational age of 36 weeks was compatible with the diagnosis of mild BPD (44,45). At an age of about 4 months of life she

of about 3 months in good clinical condition.

**Case 4** 

was discharged home.
