Hypoglycemia associated with bacteremic pneumococcal infections

Article Outline

• Summary
• Introduction
• Materials and methods
  • Patients
  • Drug susceptibility
  • Serotyping and serogrouping of isolates
  • Data analysis
• Results
  • Case identification
  • Prevalence and seasonality
  • Clinical presentation
  • Hypoglycemia
  • Other laboratory data
  • Serotype, drug susceptibility, and antimicrobial therapy
  • Course and fatality
• Discussion
• References
• Copyright

Summary 

Objectives

To evaluate the prevalence and associated presentations of hypoglycemia in bacteremic pneumococcal infections, and serotypes of the isolates.

Methods

This was a retrospective study of 70 episodes of pneumococcal bacteremia that occurred in 2004 and 2005.

Results

We found hypoglycemia (plasma glucose <3.05mmol/l)) in six (8.6%) episodes. The patients were three children (mean age 3 years 1 month; range 1 year 5 months–4 years 5 months) and three adults (mean age 73.3 years; range 63–84 years). One child with asplenia and cyanotic heart disease had primary pneumococcal bacteremia. Of the other two children, one had meningitis and the other pneumonia. All the adults had cancer with previous chemotherapy and multilobar pneumonia, which progressed rapidly to respiratory failure. All patients developed their first hypoglycemic episode within two hours after presentation. The average plasma glucose during hypoglycemia was 1.78±0.78mmol/l (range 0.33–2.94mmol/l). One child and all of the adults died. Serotypes of isolates were those usually associated with severe pneumococcal infection: 6B and 19F in the children; 3, 14, and 23F in the adults. Only the asplenic child had received pneumococcal vaccine.

Conclusions

Hypoglycemia occurred in 8.6% of bacteremic pneumococcal infections and was associated with high mortality and serotypes that cause severe invasive disease. All patients suspected of having septicemia should have their glucose checked to avoid missing hypoglycemia leading to a worsening of their already poor condition.

Keywords: Hypoglycemia, Pneumococcal bacteremia, Serotype

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Introduction 

Hypoglycemia has rarely been associated with severe infection,¹ except in cases of malaria², ³, ⁴ and shigellosis.⁵, ⁶ In 1934, Magnusson⁷ reported the first three cases of bacteremia-associated hypoglycemia in children with fulminant meningococcemia and adrenal hemorrhage. In a few subsequent case reports, hypoglycemia was found to occur in severe sepsis caused by the encapsulated bacteria Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis,¹, ⁸, ⁹, ¹⁰, ¹¹ and to be an index of grave outcome. The reported cases were young children,¹, ⁷ or adults who were splenectomized,¹, ⁸, ⁹, ¹¹ alcoholic,¹ or on chronic dialysis.¹, ⁹, ¹¹ The prevalence of hypoglycemia in pneumococcal septicemia, however, has never been studied. We conducted a retrospective study to evaluate the prevalence of hypoglycemia in patients with bacteremic pneumococcal infections, and to present the clinical course of the disease and serotypes of the pneumococcal isolates.

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Materials and methods 

Patients 

This study was conducted at a 2000-bed university hospital in northern Taiwan. We retrospectively searched the computer database of our microbiology laboratory and retrieved all patients with at least one blood culture positive for S. pneumoniae from January 2004 through December 2005. We then reviewed their charts and identified all patients with hypoglycemia (plasma glucose level of <3.05 mmol/l).¹² For the purposes of comparison, we also obtained a list of patients with bacteremia due to Staphylococcus aureus and due to Escherichia coli for the year 2004, and studied the prevalence of hypoglycemia in these two groups.

The infection that led to pneumococcal bacteremia was determined to be: (1) pneumonia, if there were clinical presentations of pneumonia and lobar pneumonic infiltrates at the initial chest radiograph, with or without concomitant isolation of S. pneumoniae from blood and sputum; (2) meningitis, if there were clinical manifestations of meningitis and isolation of S. pneumoniae from the cerebrospinal fluid; (3) spontaneous peritonitis, if there were clinical presentations of peritonitis, isolation of S. pneumoniae from ascites, and no evidence of ruptured hollow viscus. Pneumococcal bacteremia was defined as primary, if there were no clinical manifestations of local pneumococcal infection and S. pneumoniae was not isolated from sites other than blood. Septic shock was defined as previously stated.¹³ Acute respiratory distress syndrome (ARDS) was defined by bilateral pulmonary infiltrates on chest radiograph, a ratio of arterial oxygen tension (PaO₂) to the fraction of inspired oxygen (FiO₂) of 200 or less, and the absence of evidence of left atrial hypertension.¹⁴

Drug susceptibility 

All S. pneumoniae isolates were tested for drug susceptibility by the standardized disk diffusion methods.¹⁵ Minimum inhibitory concentration (MIC) tests were performed by the microdilution method for the isolates from patients with hypoglycemia.¹⁵

Antibiotic treatment was considered concordant if at least one of the antibiotics administered during the first 24hours showed full in vitro sensitivity against the isolated strain. Therapies without this criterion were defined as discordant.

Serotyping and serogrouping of isolates 

Serotyping was performed by slide agglutination with capsular typing sera and factor sera (Statens Serum Institut, Copenhagen, Denmark).

Data analysis 

The Student's t-test was used to analyze inter-group differences for the age between patients with and those without hypoglycemia. The Chi-square test was used to compare differences in the seasonal occurrence and mortality between patients with and those without hypoglycemia.

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Results 

Case identification 

During the years 2004 and 2005, there were 70 episodes (69 patients) of bacteremia due to S. pneumoniae (Table 1). Fifty episodes (71%) occurred in 49 adults (38 male, 78%), their average age being 59.8±20.0 years (range 18–92 years). Four were nosocomial. Twenty episodes occurred in children (14 male, 70%), with a mean age of 3 years 10 months (range 3 months–14 years; 70% <4 years). Pneumonia was the most common disease leading to bacteremia: 31/50 adults (62%) and 12/20 children (60%). Half of the children, and all of the adults except for one who was dead on arrival with unknown previous health condition, had an underlying disease (Table 2).

Table 1. Pneumococcal infections causing bacteremia 2004–2005.

Table 2. Major underlying diseases of patients with bacteremic pneumococcal infection.

No. (%) with known underlying disease	Underlying disease	Number (%)
Adults: 48 (98)	Solid cancer	17 (34.7)
	Leukemia and myeloma	4 (8.2)
	Chronic obstructive pulmonary disease	7 (14.3)
	Diabetes mellitus	5 (10.2)
	Alcoholic cirrhosis	4 (8.2)
	Cirrhosis, other causes	2 (4.1)
	Aortic aneurysm	3 (6.1)
	HIV infection	2 (4.1)
	Others	4 (8.2)
Children: 10 (50)	Asthma	4 (20)
	Asplenism+CHD,a VSD,b bronchiectasis, biliary atresia post-liver-transplant, angiomatosis under cytoxan, atopic dermatitis	Each 1 (5)

Prevalence and seasonality 

Plasma glucose was analyzed in 55 episodes. For the rest, the patients showed no signs of hypoglycemia. Hypoglycemia was documented in six episodes (8.6%) (Table 3). The patients were three children (one male; mean age 3 years 1 month) and three adults (all male; mean age 73.3 years). None had diabetes, alcoholism, chronic renal failure, or history of insulinoma, hypothyroidism, or hypoadrenalism. Two children were previously healthy, while all three adults had underlying cancer. The previous plasma glucose levels of all three adults were normal. All six episodes of pneumococcal bacteremia with hypoglycemia occurred in the cooler part of the year (October through March), while in adults without hypoglycemia, 24 episodes (51%, p=0.292), and in children without hypoglycemia, 10 episodes (59%, p=0.455), occurred during cooler seasons.

Table 3. Clinical and laboratory data of six patients with bacteremic pneumococcal infection and hypoglycemia.

DIC, disseminated intravascular coagulation; CRP, C-reactive protein (normal: <10mg/l); WBC, white blood cell count; y, years; m, months; d, days; M, male; F, female; CSF, cerebrospinal fluid; CHD, cyanotic congenital heart disease; ARDS, acute respiratory distress syndrome.

For the comparison with patients with bacteremia due to other pathogens, we found that in the year 2004 there were 601 episodes of bacteremia due to S. aureus and 689 episodes of bacteremia due to E. coli. In 227 (38%) of the 601 and 242 (35%) of the 689 episodes, plasma glucose levels were checked. After excluding those hypoglycemic episodes that were related to insulin administration or liver cirrhosis, we found sepsis-associated hypoglycemia in three episodes (0.5%) of bacteremia due to S. aureus and two episodes (0.3%) of bacteremia due to E. coli. These five hypoglycemic episodes occurred in January, March, April, July, and October (one in each).

Clinical presentation 

Clinical presentation differed between adults and children (Table 2). All three children had high fever at presentation (average 39.4°C). The two previously healthy children did not have shock or respiratory failure, despite one experiencing a severe meningoencephalitis and the other a pneumonia complicated with multiple lung abscesses. The only child who died was congenitally asplenic. On arrival at the emergency room, she had shock, generalized petechiae, and severe hypoxemia (oxygen saturation 37%, her usual saturation being 80% due to congenital heart disease with an intracardiac shunt). Among the six hypoglycemic patients she was the only one who had received a 23-valent pneumococcal vaccine (the conjugate vaccine was not available locally).

All three adults had pneumococcal pneumonia. On arriving at the emergency service, none was febrile or hypothermic, but all were in hypoxemia and impending respiratory failure (oxygen saturation 80%, 82%, and 74%, for cases 4, 5, and 6, respectively; Table 3). One was in shock. Two had lived in a nursing home, but all three had been ambulatory. Cases 4, 5, and 6 were receiving anti-cancer chemotherapy 8, 16, and 8 days, respectively, before the onset of pneumonia. The intermittently scheduled chemotherapy had been started 18, 7, and 3 months, respectively, before bacteremia developed. The first chest radiograph of all three adult patients showed multilobar pneumonia, which progressed rapidly to nearly complete bilateral opacification (Figure 1).

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• Figure 1. 

  Chest radiograph of patient 6 at presentation (A), showing lobar consolidation of right lower, right middle, and part of the left lower lobe, and 24hours later (B), showing rapid progression of the pneumonic process.

Hypoglycemia 

Table 3 shows plasma glucose levels of the six patients during the initial 24hours. In this period each patient had two to six measurements of plasma glucose taken, and one to three documented episodes of hypoglycemia. A total of 10 hypoglycemic episodes were documented in the six patients; none presented with cold clammy skin or sweating. The boy with meningoencephalitis and the girl with asplenism were comatose at presentation. After glucose and antimicrobial therapy, the mentality of the boy improved slowly over several days; the girl never woke up. All three adults had mild mental drowsiness at presentation that became clearer after glucose infusion. The average glucose level during hypoglycemia was 1.78±0.78 mmol/l (range 0.33–2.94 mmol/l). All six patients documented their first hypoglycemic episode within two hours after arrival. For patients 1–5, hypoglycemia was detected only in the first four hours after arrival. Patient 6, however, had recurrent, severe hypoglycemia, despite constantly being treated with intravenous glucose. The last hypoglycemic episode (0.33 mmol/l, or 6mg/dl) was documented 18hours after arrival, 17hours after antimicrobials and glucose infusion were started. The two patients who had glucose <1.67 mmol/l, or 30mg/dl (patients 3 and 6) died rapidly.

Other laboratory data 

S. pneumoniae was isolated from sputum samples of two adult patients (patients 5 and 6, Table 3). Both had a fulminant course. White blood cell count ranged from 3.55 to 26.3×10⁹/l. Tests for disseminated intravascular coagulation (DIC) were performed in four, and all were positive. The initial level of C-reactive protein (CRP) was markedly elevated (173 to 322mg/l) except in the child with cyanotic congenital heart disease (39mg/l). All three adults were hypoalbuminemic.

Serotype, drug susceptibility, and antimicrobial therapy 

Table 4 shows the serotypes, drug susceptibilities, and MICs of the six pneumococcal isolates, and the initial antimicrobial therapy the patients received. Although five of the six isolates were resistant to penicillin by disk diffusion method, MIC testing showed that only two isolates were resistant: one from the boy with meningitis with a MIC of 5μg/ml, the other from a pneumonia patient with a MIC of 4μg/ml.¹⁵ Only patient 5 received a discordant initial antimicrobial. Others were treated with concordant initial antimicrobials including third- or fourth-generation cephalosporins, with or without vancomycin.

Table 4. Serotype, serogroup, drug susceptibility, and minimal inhibitory concentration of pneumococcal isolates.

Case No.	Age	Serogroup/serotype	Drug susceptibility by disk diffusion method							MIC (μg/ml)			Initial antibiotics
			Pc	Ery	Clin	Tet	Cm	Van	Levo	Pca	Cro	Van
1	1y5m	6B	R	R	S	R	S	S	S	5 (R/R)	0.25	0.12	Van+cefotaxime
2	3y6m	6B	R	R	S	R	S	S	S	2 (R/S)	1	0.25	Cro
3	4y5m	19F	R	R	R	R	S	S	S	2 (R/S)	0.5	0.12	Van+ceftazidime
4	84y	3	S	R	R	R	R	S	S	0.03 (S/S)	0.03	0.12	Flomoxefb
5	74y	14	R	R	R	S	S	S	S	0.25 (I/S)	0.06	0.25	Amoxicillin–clavulanate
6	63y	23F	R	R	R	R	S	S	S	4 (R/R)	2	0.25	Cefepime

MIC, minimum inhibitory concentration; Pc, penicillin; Ery, erythromycin; Clin, clindamycin; Tet, tetracycline; Cm, chloramphenicol; Van, vancomycin; Levo, levofloxacin; Cro, ceftriaxone; R, resistant; S, susceptible; I, intermediate; y, years; m, months.

Course and fatality 

Among the three children, only the one with asplenia, congenital heart disease, and primary bacteremia died of fulminant septicemia (mortality 33.3%). The boy with meningitis recovered but had sequela of mental retardation and seizures. The mortality among 17 children with bacteremic pneumococcal infection but no hypoglycemia was 5.9% (1/17, p=0.677). All three adult patients progressed rapidly to respiratory failure and required mechanical ventilation. They all died of multilobar pneumonia with respiratory failure, with or without septic shock (Table 3). Compared with adult patients who had pneumonia but no hypoglycemia (n=28), the average age was not different (73.7±10.5 vs. 60.1±20.7, p=0.277), but the mortality was higher (100% vs. 25%, p=0.046).

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Discussion 

While hyperglycemia is often observed in the early phase of sepsis,¹⁶ hypoglycemia due to sepsis has been described only rarely. Sepsis has been reported to be the cause of hypoglycemia in 12% of hospitalized non-diabetic adults with hypoglycemia, other than chronic renal failure (25%), alcohol intoxication (15%), and hepatic failure (12%).¹⁷ In rat and dog sepsis, hypoglycemia is caused by an increased glucose utilization by macrophage-rich tissues (liver, spleen, lung, ileum, skin),¹⁸, ¹⁹ and decreased hepatic glucose production.¹⁹, ²⁰ The incidence of hypoglycemia in septicemia, however, has never been reported. Our study shows that hypoglycemia occurred in 8.6% of bacteremic pneumococcal infections. This is probably an underestimate, as not all patients had plasma glucose tested. Compared with bacteremia due to S. aureus or E. coli, the rate of hypoglycemia in pneumococcal septicemia was higher, probably reflecting the more invasive and fulminant nature of pneumococcal sepsis. That all six episodes of hypoglycemia associated with pneumococcal bacteremia occurred in the cooler part of the year (October to March) probably reflects the fact that invasive pneumococcal infections happen more often in cold weather.²¹ The observation that hypoglycemic episodes due to S. aureus or E. coli do not show such seasonal variation probably supports this speculation.

Our patients with hypoglycemia were young or old. The three hypoglycemic children had severe invasive disease, resulting in one death and one mental retardation. Infection-associated hypoglycemia in children is well known in malaria,², ³, ⁴ and reported rarely in shigellosis,⁵, ⁶ acute fulminant hepatitis,²² pancreatitis/gastroenteritis due to rotavirus,²³ and Reye's syndrome.²⁴ Septicemia-associated hypoglycemia in children has been described in only four cases,¹, ⁷ all due to Neisseria meningitidis. In our study it occurred in three (15%) of the 20 pediatric patients, suggesting it is probably not very rare. A routine measurement of blood glucose for any pediatric patient suspected of having sepsis may be needed, to avoid missing its presence, resulting in a worsening of an already severe disease.

The three adult hypoglycemic patients in our study all died of pneumococcal pneumonia. In the few previous case reports, hypoglycemia occurred in adult patients with septicemia due to S. pneumoniae, H. influenzae, Streptococcus pyogenes, S. aureus, Clostridium perfringens, and E. coli, with a mortality of 67%.¹, ⁸, ⁹, ²⁵, ²⁶, ²⁷ The reported patients were mostly alcoholic,¹ splenectomized,⁸, ⁹, ¹¹ on chronic dialysis,¹, ⁸, ¹¹ or cirrhotic.²⁷ Our patients, on the other hand, were receiving antineoplastic therapy for solid tumors before acquiring pneumococcal pneumonia. Patients who are receiving chemotherapy for cancer are immunosuppressed and prone to develop severe infection, including pneumococcal bacteremia.²⁸ In cancer patients, pneumococcal bacteremia is often accompanied by pneumonia, as in our patients, but can be caused by infected catheters.²⁸ The latter could be the reason that in our study, as many as 13 (26%) of 50 adult episodes were primary bacteremia, for 43% of our adult patients had cancer. Hypoglycemia has been associated with non-islet cell tumors, especially mesothelioma,²⁹ and rarely pulmonary squamous cell carcinoma.³⁰ Our patients had carcinoma of the colon, prostate, and lung, but their tumors were not likely the cause of hypoglycemia, for their previous blood glucose levels were all normal. None of our patients had alcoholism, cirrhosis, or chronic renal failure, which could cause hypoglycemia due to decreased hepatic or renal gluconeogenesis.¹⁷ Thus in our patients, bacteremic pneumococcal pneumonia was the most important factor leading to hypoglycemia. We found that plasma glucose could decline to as low as 0.33 mmol/l even after 17hours of concordant antimicrobial and glucose therapy, suggesting the necessity of monitoring blood glucose levels even after its apparent normalization.

The isolates of our patients belong to those serotypes that commonly cause invasive disease, and are covered in the 7- or 23-valent vaccines.³¹ The hypoglycemia was not associated with any specific serotype, but rather a manifestation of severe pneumococcal infection. Previous studies have shown that in invasive pneumococcal disease, serotype 3, older age, leukopenia, hypothermia, nursing home residence, pre-existing lung disease, and need for mechanical ventilation are predictors of mortality.³², ³³ Our study showed that hypoglycemia was also a marker of poor prognosis; this has often been missed, even in a large prospective study.³³ Due to the severity of such infections, the presence of hypoglycemia can be masked by the devastating condition. Delay in its detection and treatment may worsen the already poor prognosis. Other laboratory indices of poor prognosis include DIC, a known marker of sepsis.³⁴ Levels of CRP in our patients were markedly high, except in the child with cyanotic heart disease. Lower CRP levels have been reported in children with right-to-left intracardiac shunt and chronic hypoxemia than those with left-to-right shunt.³⁵ The etiology remains unknown.

Although five of the six patients received concordant antimicrobials, the mortality remained very high. Thus prevention of severe pneumococcal infection is more important than choosing appropriate chemotherapy. The asplenic child was the only one who had previously received pneumococcal vaccine. The possible reason for vaccine failure may be that the 23-valent vaccine she received could not elicit a sufficient antibody response in asplenic patients.³⁶ That all six episodes occurred in October through March probably suggests that high-risk populations should receive pneumococcal vaccine no later than early September.

As for possible causes of hypoglycemia in this population, we speculate that an overwhelming sepsis can cause hypoglycemia by: (1) increased glucose utilization by macrophage-rich tissues including liver, lung, spleen, ileum, and skin,¹⁹ and (2) depressed hepatic gluconeogenesis that has resulted from decreased sensitivity to stress hormones, and/or adrenal failure.⁷, ¹⁰, ¹⁹

In summary, hypoglycemia developed in six (8.6%) of 70 episodes of bacteremic pneumococcal infection. The three adult patients had received anti-cancer chemotherapy, and all had multilobar pneumonia and hypoxemia at presentation. One of the three children and all three adults died, although five of them had received concordant antimicrobials. All patients suspected of having septicemia should have blood glucose checked, to avoid missing hypoglycemia, resulting in a worsening of an already poor condition. The asplenic child who died was the only one who had received a pneumococcal vaccine beforehand, although all the isolates would have been covered by a 7- or 23-valent vaccine, and the infection could have been prevented.

Conflict of interest: No conflict of interest to declare.

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