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Case of the Month

September 2017

A neonate was discharged from hospital three days following delivery by Caesarean section. Although well on discharge, the mother returned to the hospital with the 2-week old neonate, who now presented with fever and poor feeding with no clear source. The neonate was admitted with a temperature of 38.5°C, pulse rate of 189 bpm and an oxygen saturation while crying, of 100%. Blood tests showed levels of C-reactive protein (CRP) of 127 mg/L (normal range: <5.0 mg/L) and procalcitonin of 10.35 ng/mL (normal range: 0.0 - 0.5 ng/mL). Cerebrospinal fluid (CSF) analysis was acellular. The chest X-ray was normal. There was no growth of any common bacterial meningeal pathogens. The neonate did not respond to meropenem and vancomycin.

A laparotomy was performed after 5 days of hospitalisation. The liver showed multiple micro abscesses from which tissue biopsies and a pus swab were collected. The Gram stain of the pus swab demonstrated scanty Gram-negative bacilli. No growth was obtained from these specimens after 5 days of culture for common bacterial pathogens. Metronidazole, azithromycin, TB treatment and fluconazole were added to treatment. The clinical microbiologist recommended that 16S rRNA PCR be performed on the specimens collected intra-operatively. The liver tissue sample was found to be positive for Legionella pneumophila. Thereafter, urine was collected which was positive for L. pneumophila serogroup 1. The baby was already on azithromycin by that stage and showed a clinical response.

Question 1 - What are the clinical features of Legionnaires’ disease?

Answer to Question 1

Fever, diarrhoea and pneumonia are common features associated with Legionnaire’s Disease. Legionellosis is typically associated with two clinically and epidemiologically distinct illnesses; Legionnaires’ disease (LD) and Pontiac fever. LD is a relatively uncommon form of pneumonia, which has a high case-fatality rate of 10%-15% (up to 30%). Symptoms include flu-like illness (high fever, muscle aches, headaches), followed by a dry cough and progression to pneumonia. Approximately 20%-50% of people with LD may also present with diarrhoea, and approximately 50% may show signs of mental confusion. If not treated, the symptoms normally worsen rapidly and may result in respiratory failure, shock, multi-organ failure and death. Situations suggesting LD include: 1) Gram stains of respiratory samples revealing many polymorphonuclear leukocytes with few or no organisms; 2) the presence of hyponatremia, 3) pneumonia with prominent extrapulmonary manifestations (e.g. diarrhoea, confusion and other neurologic symptoms), 4) failure to respond to administration of beta-lactams, aminoglycosides, or both.

Pontiac fever is a non-pneumonic illness also caused by Legionella pneumophila. It has a shorter incubation period of 12-48 hours, presents as a mild flu-like illness, and lasts up to a few days. The illness is self-limiting, and no antibiotic treatment is necessary for this illness.

Question 2 - Who is typically considered at increased risk of acquiring Legionnaires’ disease (LD)?
Answer to Question 2
  • The majority of cases of LD are isolated and sporadic, but can occur as large outbreaks with a common source.
  • LD is more commonly associated with nosocomial transmission (hospital-associated LD) and travel, although may be community-acquired.
  • Legionella spp. account for 2%-5% of community-acquired pneumonia cases in adults and are rarely detected in children.
  • LD is considerably underdiagnosed and under-reported with <5% of cases being reported to public health authorities.
  • Persons ≥50 years, current or former smokers, and those with chronic diseases including diabetes mellitus and heart or lung disease or immunosuppression / immune system disorders such as organ transplant recipients or persons receiving chemotherapy are at higher risk for LD.
Question 3 - Diagnosis of this case was aided by use of 16S ribosomal RNA (rRNA) PCR and sequencing. For which pathogens can this method be used for aetiological identification?
Answer to question 3

16S ribosomal RNA (rRNA) gene sequences contain highly conserved primer binding sites, as well as internal hypervariable regions that can provide species-specific signature sequences useful for identification of bacteria. As a result, 16S rRNA gene sequencing has become a rapid and relatively cost-effective alternative to phenotypic methods of bacterial identification. More common methods of Legionella diagnosis include:
  • Urinary antigen test detecting Legionella pneumophila serogroup 1;
  • Culture from a lower respiratory tract specimen detecting all Legionella spp.;
  • Real-time PCR on lower respiratory tract specimens detecting all Legionella spp.
Question 4 - Legionnaires’ disease is a notifiable condition in South Africa. Why is it important to promptly notify cases to the relevant health authority?
Answer to Question 4

Prompt notification of public health authorities of any suspected or confirmed case is critically important for detecting epidemics of the disease and identifying environmental sources of infection. Legionella is not normally transmitted from person-to-person, and there has only been one case of person-to-person transmission documented.
If a confirmed or probable case is detected, the following steps should be taken at least within 7 days of diagnosis:
  • The clinician must complete the Notifiable Medical Conditions (NMC) case notification form as soon as possible and send to the NMC focal person or manager at the health establishment, who is responsible for notification to the relevant authorities.
  • An LD case-investigation form should be completed. This will require an interview with the patient or close relative to identify potential sources of infection.
  • The diagnostic laboratory or microbiologist submit specimens and isolates as soon as possible to the Centre for Respiratory Diseases and Meningitis (CRDM), National Institute for Communicable Diseases (NICD).
  • Further investigations will be conducted to identify the source of infection, and environmental sampling conducted when considered necessary.
For this neonatal case, environmental water sampling was performed at the hospital and at the home of the patient. The clinical isolates cultured from the neonate were identified as Legionella pneumophila SG1 sequence type (ST) 1. This same sequence type was isolated from water samples collected from the hospital and the patient’s household. Whole-genome sequencing of the isolates indicated that the clinical isolates were more closely related to isolates obtained from the hospital water system, and that the hospital was the likely source of Legionella infection in this case.

Question 5 – What is the recommended treatment for Legionnaires’ disease?
Answer to Question 5
  • Legionella spp, which are intracellular pathogens, do not respond to β-lactam antibiotics such as penicillins and cephalosporins and therefore will not be covered by empiric therapy for community-acquired pneumonia in South Africa.
  • Patients require early treatment from an appropriate range of antibiotics which can penetrate cells, such as macrolide or fluoroquinolone antibiotics.
  • Recommended duration for antimicrobial therapy is 7 to 10 days, with up to 21 days recommended for immunosuppressed patients.
  • It is important for clinicians to have a high index of suspicion for legionellosis and request appropriate diagnostic tests, especially in the setting of potential hospital-acquired cases of infection.
  • Molecular diagnostic methods such as PCR and 16S rRNA sequencing may be useful methods for rapid diagnosis of uncommon and/or fastidious bacterial pathogens.
Question 6 - Which settings should have Legionella prevention and control programmes in place?
Answer to Question 6

Large buildings with complex plumbing systems are at high risk for growth of Legionella spp. Health care facilities should establish effective water management programmes for prevention and control of Legionella spp.

References
  1. Mercante JW, Winchell JM. Current and Emerging Legionella Diagnostics for Laboratory and Outbreak Investigations. Clin Microbiol Rev 2015;28:95-133.
  2. Legionnaires’ disease: NICD Recommendations for Diagnosis, Management and Public Health Response available at: http://www.nicd.ac.za/assets/files/NICD_guidelines_for_Legionella_v_1_2_3_June_2016_Final(1).pdf.
  3. Notifiable Medical Conditions (NMC) case notification form available at: http://www.nicd.ac.za/index.php/nmc/notifiable-medical-conditions-nmc-case-notification-form/.
  4. Wolter N, Carrim M, Cohen C, Tempia S, Walaza S, Sahr P, de Gouveia L, Treurnicht F, Hellferscee O, Cohen AL, Benitez AJ, Dawood H, Variava E, Winchell JM, von Gottberg A. Legionnaires' Disease in South Africa, 2012-2014. Emerg Infect Dis 2016;22:131-33.
  5. Soda EA et al., Vital Signs: Health Care-Associated Legionnaires’ Disease Surveillance Data from 20 States and a Large Metropolitan Area – United States, 2015. MMWR 2017; 66: 584-589.
  6. Granseth G et al., Two Cases of Legionnaires’ Disease in Newborns After Water Births – Arizona, 2016. MMWR 2017; 66:590-591.
  7. Wei SH, et al., Nosocomial Neonatal Legionellosis Associated with Water in Infant Formula, Taiwan. Emerg Infect Dis 2014; 20: 1921-4.
  8. Yiallouros PK et al., First Outbreak of Nosocomial Legionella Infection in Term Neonates Caused by a Cold Mist Ultrasonic Humidifier. Clin Infect Dis 2013; 57: 48-56.
  9. Correia AM et al., Probable Person-to-Person Transmission of Legionnaires' Disease. N Engl J Med 2016; 374: 497-98.

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