CG.CP.MP.02 Concert Infectious Disease: Multisystem Testing
2025.1
Date of Last Revision: 11/2024

CENTENE
Corporation

Coding Implications
Revision Log

CONCERT INFECTIOUS DISEASE:

MULTISYSTEM TESTING

See Important Reminder at the end of this policy for important regulatory and legal
information.

OVERVIEW

Some pathogens cause infections with symptoms that affect a primary body system, while others
cause infections that affect multiple body systems. This policy outlines the appropriate use of
tests for pathogens that can cause multisystem symptoms and/or infections. Tests for pathogens
that infect multiple body systems can be targeted to detect a specific pathogen(s) or non-targeted
to broadly detect nucleic acid from any potential pathogen.

Cytomegalovirus (CMV) is a common infection that does not usually cause problems in healthy
individuals. However, it is of particular concern in individuals with weakened immune systems
(e.g., organ transplant recipients), and can lead to signs and symptoms such as fever, sore throat,
swollen glands, extreme fatigue/malaise, mononucleosis, or hepatitis, and increased risk of poor
outcomes (morbidity/mortality). Additionally, infections during pregnancy can lead to infection
of the fetus (congenital CMV infection). One in 5 babies with congenital CMV infection will
have long term health impacts, such as hearing loss, vision impairment, or small head size
(microcephaly).

Metagenomic sequencing, a newer, more generalized technique, can detect multiple organisms’
genomes within a single specimen. While these new tests have potential benefits, challenges
remain to be explored prior to routine clinical adoption, such as whether they can reliably discern
predominantly host genomic material from a small amount of pathogen genomic material or
active infection from colonization, among others.

This policy is intended for use in the outpatient setting.

POLICY REFERENCE TABLE

CRITERIA

It is the policy of health plans affiliated with Centene Corporation® that the specific tests noted
below are medically necessary when meeting the related criteria:

CYTOMEGALOVIRUS TESTS

METAGENOMIC SEQUENCING TESTS

Untargeted Metagenomic Sequencing Tests for Pathogen Detection

I. Untargeted metagenomic sequencing tests for pathogen detection are considered
investigational for all indications.

NOTES & DEFINITIONS

1. Congenital CMV infection in a newborn can be characterized by features including
   rash, jaundice (yellowing of the skin or whites of the eyes), microcephaly (small head),
   low birth weight, hepatosplenomegaly (enlarged liver and spleen), seizures, and retinitis
   (damaged eye retina).

2. Ultrasound findings consistent with CMV infection may include microcephaly
   (smaller than normal head size), calcifications of the brain and liver, echogenic bowel,
   hepatosplenomegaly, various abnormalities of the brain (ventriculomegaly,
   intra/parenchymal cysts, abnormalities of the corpus callosum, cortical malformations),
   and intraventricular hemorrhages.

3. Symptoms of active CMV infection can include fever, sore throat, swollen glands,
   extreme fatigue/malaise, mononucleosis, or hepatitis.

4. Symptoms and signs of mononucleosis can include malaise/fatigue, sweats, sore throat,
   anorexia, nausea, headache, chills, swollen glands, fever, or splenomegaly.

BACKGROUND AND RATIONALE

CYTOMEGALOVIRUS TESTS

Cytomegalovirus (CMV) Antibody Tests

Centers for Disease Control and Prevention

“For most people, CMV infection is not a serious health problem. However, certain groups are at
a high risk for serious complications from CMV infections:

1. Infants infected in utero (congenital CMV infection)
2. Very low birth weight and premature infants
3. People with compromised immune systems, such as from organ and bone marrow
   transplants, and people infected with human immunodeficiency virus (HIV)”

The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-
organ Transplantation

The following pertinent recommendations are made in the consensus guidelines:

• We recommend performing donor and recipient CMV IgG serology pretransplantation
  for risk stratification (strong, high).*

• In children 12 months and younger with seropositivity, nucleic acid testing may be warranted
  to further confirm results, as false-positives may occur due to passive antibodies transferred via
  breastfeeding. (p. 903)

American Academy of Family Physicians

“The possibility of acute CMV infection should be explored if a negative heterophile antibody
test rules out EBV mononucleosis. The best diagnostic test for establishing CMV mononucleosis
is serology for CMV IgM antibodies, which should be positive in the majority of patients during
the symptomatic phase of the illness.” (p. 521)

Cytomegalovirus (CMV) Nucleic Acid/PCR or Antigen Detection Tests

The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-
organ Transplantation

The following pertinent recommendations are made in the consensus guidelines:

• We recommend performing donor and recipient CMV IgG serology pretransplantation
  for risk stratification (strong, high).*

• We recommend using QNAT calibrated to the WHO standard for diagnosis, surveillance
  to guide preemptive antiviral treatment, and for therapeutic monitoring due to the ability
  to harmonize and standardize these tests (strong, high).

• We recommend when monitoring response to antiviral therapy, that QNAT is performed
  weekly (strong, moderate).

• In children 12 months and younger with seropositivity, nucleic acid testing may be warranted
  to further confirm results, as false-positives may occur due to passive antibodies transferred via
  breastfeeding. (p. 903-904)

Society for Maternal-Fetal Medicine

In the 2016 Consult Series #39, the SMFM recommended the following:

• Diagnosis of suspected primary CMV infection in pregnant women should be either by
  IgG seroconversion or with positive CMV IgM, positive IgG, and low IgG avidity (grade
  1B)
• Amniocentesis is the best option for prenatal diagnosis of fetal congenital CMV infection
  and should be performed at >21 weeks of gestation and >6 weeks from maternal infection
  (grade 1C)
• Routine screening of all pregnant women for evidence of primary CMV infection is NOT
  recommended at this time (grade 1B) (p. B5)

Centers for Disease Control and Prevention

The CDC states that the standard laboratory test for evaluation of suspected congenital CMV
infection is polymerase chain reaction (PCR) on saliva, with subsequent confirmatory testing on
urine.

The CDC lists the following symptoms that may be present in about 10% of infants with
congenital CMV:

• Rash
• Jaundice (yellowing of the skin or whites of the eyes)
• Microcephaly (small head)
• Low birth weight
• Intrauterine growth restriction (low weight)
• Hepatosplenomegaly (enlarged liver and spleen)
• Seizures
• Retinitis (damaged eye retina)

Additionally, they list the following long-term problems that may occur in about 40 to 60% of
infants born with signs of congenital CMV disease:

• Hearing loss
• Vision loss
• Intellectual disability
• Microcephaly (small head)
• Lack of coordination or weakness
• Seizures

It is important to note that some infants with hearing loss may not be detected by newborn
hearing tests.

World Health Organization

The WHO defines very low birth weight as below 1.5 kg or 1500 grams, and a preterm infant as
one who was born before 37 0/7 weeks of gestation. (p. vii)

UpToDate

The UpToDate article entitled “Cytomegalovirus infection in pregnancy,” includes the following
list of ultrasound markers as those that are suggestive, but not diagnostic, of a fetal CMV
infection:

• Periventricular calcifications
• Cerebral ventriculomegaly
• Microcephaly
• Pseudocysts, periventricular or adjacent to the occipital or temporal horn
• Hyperechogenic fetal bowel
• Fetal growth restriction
• Ascites
• Pleural and/or pericardial effusion
• Hepatosplenomegaly
• Hepatic calcifications
• Polymicrogyria
• Cerebellar hypoplasia
• Large cisterna magna
• Amniotic fluid abnormalities (oligohydramnios or polyhydramnios)
• Hydrops
• Placental thickening and enlargement, heterogeneous appearance, calcifications

METAGENOMIC SEQUENCING TESTS

Untargeted Metagenomic Sequencing Tests for Pathogen Detection

Gu, Miller, and Chiu

In their 2019 review, Gu, Miller, and Chiu state the following: “While the emergence of these
new mNGS technologies is exciting, their rapid evolution often outpaces clinical test validation
and the comprehensive collection of clinical evidence. Similar to other types of clinical testing,
the application of these new diagnostic testing methods should be accompanied by rigorous
clinical studies that (a) demonstrate clinical utility, (b) guide usage, and (c) uncover potential
areas of misinterpretation. As with any new technology, the clinical adoption of mNGS testing
will take time as providers become familiar with it and new guidelines are developed.” (p. 16)

Casto, Fredricks, and Hill

In their 2021 review of 36 studies on Untargeted Metagenomic Sequencing for detecting
pathogens in immunocompromised populations, Casto et al. focused on the clinical performance
findings from 14 of these studies.

The authors note that studies on clinician-ordered metagenomic next-generation sequencing for
pathogen identification (mNGSpi) show that these tests had clinical impact in a small minority of
cases. This discrepancy arises from differences in study designs: clinician-ordered tests are often
used after other testing and treatments in difficult cases, while researcher-selected cohorts use
mNGSpi earlier and on less challenging cases. Current evaluations of clinical impact, based on
chart reviews and clinician reports, are subjective and potentially biased. Moreover, all studies so
far lack control groups, limiting the reliability of conclusions about mNGSpi’s clinical impact (p.
10-11)

There are no professional guidelines or recommendations we identified to support the use of
these tests.

Coding Implications

This clinical policy references Current Procedural Terminology (CPT®). CPT® is a registered
trademark of the American Medical Association. All CPT codes and descriptions are copyrighted
2024, American Medical Association. All rights reserved. CPT codes and CPT descriptions are
from the current manuals and those included herein are not intended to be all-inclusive and are
included for informational purposes only. Codes referenced in this clinical policy are for
informational purposes only. Inclusion or exclusion of any codes does not guarantee coverage.

Providers should reference the most up-to-date sources of professional coding guidance prior to
the submission of claims for reimbursement of covered services.

CG:CP.MP.02 Concert Infectious Disease: Multisystem Testing
2025.1
Date of Last Revision: 11/2024

| Nucleic Acid/PCR or Antigen Detection Tests; Cytomegalovirus (CMV) Antibody Tests. For Untargeted Metagenomic Sequencing Tests for Pathogen Detection: Added Bacteria, Viruses, Fungus, and Parasite Metagenomic Sequencing, Spinal Fluid (MSCSF) (Mayo Clinic) to the Policy Reference Table and updated related background. References reviewed and updated. | |

CG:CP.MP.02 Concert Infectious Disease: Multisystem Testing
2025.1
Date of Last Revision: 11/2024