You may want to contact Dr Cunningham and get her take, but my understanding is that her panel can also come back positive when lyme, not strep, is the trigger. Some strains of strep have an outer protein on their cell surface called an M protien. Lyme spirochettes share this M protein and if memory serves, some cells in the human body - cells on heart valves and cells in the basal ganglia - have very similar looking M proteins. This is what might cause the autoimmune reaction of molecular mimicry.
So what your Cunningham results will tell you is whether the body is making auto-antibodies that target on of 4 neuronal receptors in the brain - D1 or D2 receptors, anti-lysogangliosides or tubulin. It also measures one kind of inflammation marker called a cytokine - specifically the cytokine called CaMK II. These markers tell you whether the neuropsych symptoms you're seeing could be auto-immune. But they do not tell you what type of infection is causing the body to make these antibodies against itself and its own receptors. It could be strep, or it could be lyme, or it could be some other infection.
If the Cunningham results come back positive, you'll know its PANS but your treatment options will be similar to what you've already done for lyme - long term, combo antibiotics (hopefully your LLMD has done combos of abx and not just one type at a time. If he hasn't, this could be the cause of the relapse). Prednisone probably wouldn't be an ideal option if there's a possibility that lyme is still in the picture. Some Pans/lyme kids are helped by IVIG. Others have a hard time handling the sudden powering up of the immune system - it caused a huge herx for my son when he had IVIG prior to our discovering lyme.
Those of us who have kids with lyme have generally followed ILADS treatment protocols and slowly gotten our kids well. If your son has been on abx for 3yrs, I'd test for strep (ASO and Anti-DNase B blood tests) but a lyme relapse sounds worth exploring, regardless of the Cunningham results. The Cunningham Panel doesn't mean that strep is your culprit.
If you suspect a virus, antibiotics wouldn't help. Have you explored viral treatments with your LLMD? Have you done a stool test to see what, if anything, is amiss in the gut?
Also, depression and bipolar symptoms can be caused by nutritional imbalances in a process called methylation. Methylation is who the body takes raw ingredients (the B vitamins, minerals, other food nutrients) and converts them into neurotransmitters. If you have genetic mutations that prevent the "methylation genes" from working properly, you can become deficient in various neurotransmitters.
When the body has a major chronic illness to fight (like lyme of recurrent/chronic strep), it has a limited amount of physical resources available. If it needs to divert resources like vitamin D, zinc, etc toward the immune system, that means it has less of those nutrients on hand to synthesize neurotransmitters. For example, Vitamin D is used in bone development, to aid the immune system, to regulate sleep cycles and to synthesize dopamine. If the body has to redirect its D toward the immune system, you could see disruptions in sleep or dopamine (e.g. depression or anger) because there isn't enough D to go around.
So if there's any sort of chronic infection, or if a less than perfect diet prevents the body from recovering from nutritional deficiencies caused by an illness, you can see neuropsych symptoms even after the infection is under control. And simply taking a multivitamin won't fix things. When you have genetic mutations preventing smooth sailing, you need specific forms of vitamins that will bypass the mutation roadblocks in your unique chemical plant. I've seen huge improvements in my kids' symptoms and behaviors since addressing methylation issues - even after chronic infections were addressed.
So I hope the Cunningham Panel gives you a better sense of what's going on, but realize it's the tip of the ice berg. The good news is that there are multiple paths you can take to get your son back on track.